Get Our e-AlertsSubmit Manuscript
Research / 2020 / Article

Review Article | Open Access

Volume 2020 |Article ID 6925296 |

Zichao Luo, Melgious Jin Yan Ang, Siew Yin Chan, Zhigao Yi, Yi Yiing Goh, Shuangqian Yan, Jun Tao, Kai Liu, Xiaosong Li, Hongjie Zhang, Wei Huang, Xiaogang Liu, "Combating the Coronavirus Pandemic: Early Detection, Medical Treatment, and a Concerted Effort by the Global Community", Research, vol. 2020, Article ID 6925296, 35 pages, 2020.

Combating the Coronavirus Pandemic: Early Detection, Medical Treatment, and a Concerted Effort by the Global Community

Received19 Apr 2020
Accepted20 Apr 2020
Published16 Jun 2020


The World Health Organization (WHO) has declared the outbreak of 2019 novel coronavirus, known as 2019-nCoV, a pandemic, as the coronavirus has now infected over 2.6 million people globally and caused more than 185,000 fatalities as of April 23, 2020. Coronavirus disease 2019 (COVID-19) causes a respiratory illness with symptoms such as dry cough, fever, sudden loss of smell, and, in more severe cases, difficulty breathing. To date, there is no specific vaccine or treatment proven effective against this viral disease. Early and accurate diagnosis of COVID-19 is thus critical to curbing its spread and improving health outcomes. Reverse transcription-polymerase chain reaction (RT-PCR) is commonly used to detect the presence of COVID-19. Other techniques, such as recombinase polymerase amplification (RPA), loop-mediated isothermal amplification (LAMP), clustered regularly interspaced short palindromic repeats (CRISPR), and microfluidics, have allowed better disease diagnosis. Here, as part of the effort to expand screening capacity, we review advances and challenges in the rapid detection of COVID-19 by targeting nucleic acids, antigens, or antibodies. We also summarize potential treatments and vaccines against COVID-19 and discuss ongoing clinical trials of interventions to reduce viral progression.

1. Introduction

The recent global outbreak of COVID-19 has led to a public health emergency. As of April 23, 2020, over 2.6 million confirmed cases were reported to WHO from 213 countries and territories [1]. On January 30, 2020, WHO declared the COVID-19 outbreak as the sixth public health emergency of international concern, following H1N1 (2009), Polio (2014), Ebola in West Africa (2014), Zika (2016), and Ebola (2019) [2]. The rapid global expansion and rising fatalities have raised grave concerns on the viral spread across the globe. With the rapid increase in the number of confirmed cases, WHO classified the global COVID-19 outbreak as a pandemic on March 11, 2020 [3]. COVID-19 can spread from person-to-person and animal, and transmission of infection may occur with exposure to symptomatic patients or asymptomatic individuals.

Coronaviruses (CoVs) (corona: crown-like shape) are enveloped, single-stranded RNA viruses that belong to the order Nidovirales in the subfamily Coronaviridae. CoVs are divided into four genera: alpha (α), beta (β), gamma (γ), and delta (δ) (Figure 1(a)) [4]. Alpha- and beta-CoVs infect mammals, while gamma- and delta-CoVs primarily infect birds [5]. Before December 2019, six types of CoVs had infected humans, including two α-CoVs (HCoV-229E and HCoV-NL63) and four β-CoVs (HCoV-OC43, HCoV-HKU1, SARS-CoV, and MERS-CoV). The first two β-CoVs (HCoV-OC43 and HCoV-HKU1) mainly cause self-limiting upper respiratory infections, while the other two β-CoVs (SARS-CoV and MERS-CoV) are mostly associated with severe respiratory illness [6, 7]. Full-genome sequence analysis of 2019-nCoV confirms that it is a β-CoV, distinct from SARS-CoV and MERS-CoV [8]. Investigations reveal that 2019-nCoV shares ~80% sequence identity with SARS-CoV while maintaining ~89% nucleotide identity to the SARS-like CoVs (ZC45 and ZXC21) from bats [9]. A recent report suggests that a bat CoV (RatG13) is 96% identical to 2019-nCoV [10].

A typical CoV genome is a single-stranded, positive-sense RNA (+ssRNA) (~30 kb) enclosed by a 5-cap and 3-poly-A tail [11]. The genome size of 2019-nCoV is 29,891 nucleotides, encoding 9860 amino acids, with a G+C content of 38% [12]. The 2019-nCoV genome contains two flanking untranslated regions (UTRs) on 5- and 3-terminals, one single long open reading frame 1ab (ORF1ab) encoding a polyprotein and at least five other ORFs encoding structural proteins, and eight accessory proteins (Figure 1(c)). The first ORF (ORF1a/b) is about two-thirds of the whole-genome length and encodes the 16 nonstructural proteins (nsp1-16). The other one-third of the genome contains four ORFs encoding the spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins, whereas other ORFs encode accessory proteins (Figure 1(b) and (c)). Most of the nonstructural proteins are essential for 2019-nCoV replication, while structural proteins are responsible for virion assembly and viral infection [12, 13]. The M and E proteins are required in viral assembly, while the N protein involves RNA genome assembly.

The S protein, a surface-located trimeric glycoprotein of CoVs, is the primary determinant of CoV tropism, as it binds to the membrane receptor on host cells, mediating viral and cellular membrane fusion [14]. The S protein of 2019-nCoV reportedly binds to angiotensin-converting enzyme 2 (ACE2), a homolog of ACE on host cell membranes, contributing to 2019-nCoV cell invasion [15]. Moreover, this particular S protein shows a higher binding affinity to ACE2 than the S protein of SARS-CoV, enabling 2019-nCoV to invade host cells more effectively [16, 17]. Recently, a transmembrane glycoprotein, CD147, also known as Basigin or EMMPRIN, has been confirmed as another receptor for binding of the 2019-nCoV S protein, thereby mediating viral invasion [18].

The E protein is an integral membrane protein that regulates viral life cycles, including pathogenesis, envelope formation, assembly, and budding [1921]. Among the four structural proteins, protein E appears to have the highest antigenicity and the most significant potential as an immunogenic target, highlighting the possibility of developing protein E-derived peptides as a 2019-nCoV vaccine [22]. Systemic studies of proteins S and E have inspired scientists to take creative approaches to design anti-COVID-19 drugs.

Although some COVID-19 patients show no symptoms, most patients have some common symptoms such as fever, cough, fatigue, sputum production, shortness of breath, sore throat, and headache. In some severe cases, infections can cause pneumonia, severe acute respiratory syndrome, kidney failure, and death. According to the WHO-China joint report [23], on average, people infected with 2019-nCoV develop mild respiratory symptoms and fever, 5-6 days after infection (mean incubation period, 5-6 days; range, 1-14 days). People over 60 years of age and those with hypertension, diabetes, or cardiovascular diseases are at high risk for severe illness and death. In comparison, children under 19 years appear to be infected minimally by 2019-nCoV (around 2.4% of all reported cases). Based on the Chinese Center for Disease Control and Prevention (China CDC) report (from 72,314 patient records, dated 11 February 2020), among the confirmed cases, 86.6% of patients are 30-79 years of age, 80.9% of patients have mild-to-moderate disease, 13.8% have a severe illness, and 6.1% are critically ill [24]. Notably, the mortality rate of children under 19 years is 0.2%, while people aged over 80 years have the highest mortality rate of 14.8%.

Currently, there are no effective antiviral drugs or specific vaccines against COVID-19. Thus, there is an urgent need for rapid detection to prevent further spread, to reduce the intensity of the pandemic, and to slow the increase in cases. Recently, several new technologies, including LAMP-LFA, RPA-LFA, RPA-CRISPR, and other nanomaterial-based IgG/IgM kits, have been adopted for 2019-nCoV detection. A significant number of drug candidates, including chemical drugs, biological drugs, nutritional interventions, and traditional Chinese medicine (TCM), have been proposed for clinical trials after the 2019-nCoV outbreak. In this review, we concentrate on the most significant developments in 2019-nCoV detection and provide an overview of medical treatments and vaccines currently in development to combat and contain the disease.

2. 2019-nCoV Detection

According to the Diagnosis and Treatment Guidelines for COVID-19 (7th edition), COVID-19 cases can be divided into suspected cases and confirmed cases [25]. Diagnostic methods for 2019-nCoV are determined by the intrinsic properties of the virus and biomarkers that hosts exhibit after infection. These biomarkers include viral proteins and nucleic acids, as well as antibodies induced in response to viral infection. The most common 2019-nCoV detection methods include viral nucleic acid detection and serum antibody (IgG or IgM) detection. A confirmed case should have at least one of the following criteria: (i) a positive result for 2019-nCoV nucleic acid, using real-time PCR tests from respiratory or blood samples; (ii) a high homogeneity between viral gene sequencing from respiratory or blood samples and known 2019-nCoV; and (iii) serum samples positive for IgM or IgG to 2019-nCoV, or seroconversion in IgG, or a fourfold or more significant increase in IgG antibody titer to 2019-nCoV in the recovery phase than in the acute phase [25].

2.1. Nucleic Acid Targeting
2.1.1. High-Throughput Sequencing (2nd-Generation Sequencing)

High-throughput sequencing (HTS) technology contains various strategies that depend on a combination of library preparation, sequencing and mapping, genome alignment, and data analysis [26] (Figure 2(a)). Unlike the 1977 Sanger sequencing method (1st-generation sequencing) [27], 2nd-generation sequencing has been widely applied in genome sequencing, transcriptional profiling (RNA-seq) disease mapping, and population genetic studies. The whole-genome nucleotide sequence of 2019-nCoV was identified and compared with the full-length genome sequence of coronavirus from bats [10] through HTS. HTS-based technology is also applied to detect 2019-nCoV. For example, Wang et al. developed a HTS method based on nanopore target sequencing (NTS) by harnessing the benefits of target amplification and long-reads for real-time nanopore sequencing [28].

This NTS strategy detects 2019-nCoV with higher sensitivity (100-fold) than standard qPCR, simultaneously with other respiratory viruses within 6-10 h. Moreover, all targeted regions can be identified by NTS in higher copies of samples (1000-3000 copies/mL) within 10 min, indicating the potential for rapid detection of an outbreak in the clinic. For 1 h sequencing data, reads mapped to 2019-nCoV differed remarkably from those of negative controls in all targeted regions at concentrations ranging from 10 to 3000 copies/mL. Importantly, NTS can identify mutated nucleic acids. However, the NTS platform cannot readily detect highly degraded nucleic acid fragments that are less than 200 base pairs in length [29]. Moreover, the strategy requires tedious sample preparation and lengthy turnaround time.

Although HTS technology provides fast, low-cost DNA sequencing, it is not suitable for detection in clinics. On the other hand, the HTS strategy may be suitable for amplicon sequencing or de novo sequencing of a whole genome [30].

2.1.2. Real-Time Reverse Transcription-Polymerase Chain Reaction (RT-PCR)

RT-PCR is considered the gold standard to detect nucleic acids extracted from 2019-nCoV specimens qualitatively. Positive results indicate infection with 2019-nCoV. RT-PCR is an advanced technique for coronavirus detection because of its optimized sensitivity, specificity, and simplicity for quantitative assay [31, 32]. It provides accurate and reliable identification for confirmed and suspected cases. There are many commercial 2019-nCoV detecting kits with oligonucleotide primers and probes (SYBR Green or TaqMan chemistries) for detecting double genes of 2019-nCoV (nucleocapsid N gene and ORF1ab/E/ORF1b/S gene). This strategy usually requires four steps: sample collection (respiratory swabs), sample preparation (RNA isolation), one-step qRT-PCR, and data analysis (Figure 2(b)) [33]. The evaluation procedure typically lasts 4-6 h. Recently, Roche (Indiana, USA) developed two automated cobas® 2019-nCoV test systems: cobas® 6800 and cobas® 8800 (approved in testing patient samples by the US FDA), which can process up to 384 results and 1056 results in an 8-hour shift, respectively [34]. The tests produce results in about 3.5 h and can process up to 4128 results in 24 h, boosting screening capacity to help restrain the sudden growing epidemic in the USA. RT-PCR is widely applicable to 2019-nCoV detection in the clinic, but limitations of this technology are obvious, such as high false-negative rate and low sensitivity. False-negative results may occur due to the following factors: first, mutations in the primers and probe-target regions in the 2019-nCoV genome [32]; second, low viral load present in test specimens, improper extraction of nucleic acid from clinical samples, or inappropriate restrictions on sample collection, transportation, or handling [31]. Real-time RT-PCR has been adopted as the gold standard diagnostic approach for 2019-nCoV worldwide. However, RT-PCR is time-consuming (4-6 h) and requires well-equipped laboratories and skilled technicians, thereby limiting full deployment in developing countries.

2.1.3. Reverse Transcription- Isothermal Amplification (RT-IAMP)-Based Detection

Isothermal amplification technology has been developed to eliminate the need for a high-precision instrument in RT-PCR assays. This approach can amplify DNA at isothermal conditions without a thermocycler [35]. There are mainly four isothermal amplification technologies for nucleic acid detection: LAMP, RPA, nucleic acid sequence-based amplification (NASBA), and transcription-mediated amplification (TMA) [36]. In NASBA and TMA assays, input RNA is converted to a double-stranded DNA intermediate with a promoter region. Detection of RNA using DNA polymerase-based amplification requires a reverse transcriptase step. LAMP and RPA do not require thermal or chemical melting with the aid of enzymes. Combined with a visual detection platform, such as a lateral flow assay (LFA) or organic dyes, LAMP and RPA have been widely employed in viral detection kits.

LAMP is a rapid, one-step amplification technique that amplifies nucleic acids with high sensitivity and specificity at an optimal temperature of 65°C [37]. LAMP processing comprises three steps: an initial step, a cycling amplification step, and an elongation step (Figure 3(a)). LAMP employs six primers to amplify targeted genes by creating stem-loop structures that promote new DNA synthesis using a DNA polymerase with strand displacement activity. The two inner primers (FIP, BIP) and two outer primers (F3, B3), along with loop structures (LF, LB), create multiple initiating sites in the growing DNA products, enabling rapid amplification. LAMP is also highly specific since the amplification reaction occurs only when the primers correctly recognize all six regions. A reverse transcriptase step is included in the LAMP reaction to allow RNA targets to be detected [38].

RT-LAMP offers improved sensitivity and specificity in screening SARS-CoV, HCoV-NL63, and MERS-CoV compared to conventional real-time RT-PCR [3941]. Recently, Yu et al. used a commercial LAMP kit to amplify fragmented ORF1ab genes of 2019-nCoV (Figure 3(b) and (c)) [42]. They optimized the LAMP system through incubation at 65°C for different periods using a 2019-nCoV-positive RNA sample as the template. Results require a 15 min reaction time at 65°C, and detection sensitivity is comparable to that of the TaqMan-based qPCR approach (10 copies). RT-LAMP employs two additional protocols for 2019-nCoV RNA detection. Park et al. performed RT-LAMP at 65°C for 40 min to identify the nsp3, S, and N genes of 2019-nCoV using colorimetric detection [43]. The sensitivity of this RT-LAMP assay was 100 copies of 2019-nCoV RNA. The other RT-LAMP protocol was conducted at 63°C for 30 min to detect the ORF1ab, E, and N genes simultaneously [44]. The results confirmed the specific nature of ORF1ab and the high sensitivity of the N gene. Based on an analysis of 208 clinical specimens, the sensitivity of this RT-LAMP was similar to conventional RT-PCR, and the specificity was 99%. Interestingly, EI-Tholoth et al. designed a two-stage isothermal amplification procedure by combining RPA (37°C) with LAMP (63°C) to detect synthesized DNA fragments of 2019-nCoV [45]. The test was performed in closed tubes within 1 h using either fluorescence or colorimetric detection. This method has a sensitivity of 100 times better than conventional LAMP and RT-PCR, suggesting a rapid, sensitive, point-of-care test for use at home.

RPA is an isothermal DNA amplification method that utilizes a specific combination of enzymes and proteins (recombinase, single-strand binding (SSB) protein, and strand-displacing DNA polymerase) to amplify target genes rapidly at a constant low temperature between 25 and 42°C in as little as 15 min [46]. RPA usually requires four steps to achieve DNA amplification: formation of a recombinase-primer complex, strand invasion, D-loop formation (stabilized by SSB, DNA polymerization through the use of strand-displacing DNA polymerase), and DNA amplification (Figure 3(d)) [47]. Results of RPA can be detected by agarose gel electrophoresis, quantitatively measured using TwistAmp probes, or simply applied in lateral flow assays. Apart from DNA target amplification, RPA formats have been developed for the detection of RNA targets (RT-RPA) by adding a reverse transcriptase enzyme to reaction mixtures [48]. Because RPA- (RT-RPA-) based detection achieves more rapid and sensitive results and operates efficiently, it has been widely adopted to detect animal and human pathogens, such as hand, foot, and mouth disease (HFMD) virus, human immunodeficiency virus (HIV), bovine coronavirus, or MERS-CoV [4952]. Currently, RPA has been applied to detect 2019-nCoV, in combination with other technologies, such as CRISPR or microfluidic technology.

2.1.4. Clustered Regularly Interspaced Short Palindromic Repeat- (CRISPR-) Based Detection

The CRISPR-associated protein 9 (Cas9) system (CRISPR/Cas9) is a revolutionary gene-editing toolbox that can modify target genes with high precision and that can control various types of genetic diseases in preclinical studies [5356]. Due to the collateral nucleic acid cleavage activity of Cas effectors, CRISPR/Cas systems have also been widely used in nucleic acid detection with fluorescent and colorimetric signals [56]. There are mainly two kinds of CRISPR/Cas systems for diagnostics, based on the cutting activity of Cas protein on nucleic acids outside of the gRNA target site: the CRISPR/Cas13a and CRISPR/Cas12a systems.

The CRISPR/Cas13a system (specific high-sensitivity enzymatic reporter unlocking (SHERLOCK)) was developed by Zhang’s group, based on the collateral effect of an RNA-guided and RNA-targeting CRISPR effector, Cas13a (Figure 4(a)) [57, 58]. The detection system is highly sensitive and specific because it is capable of single-molecule nucleic acid detection. Subsequently, they developed an enhanced SHERLOCK version 2 (SHERLOCKv2) detection system with a 3.5-fold improvement in detection sensitivity and lateral flow readout. SHERLOCKv2 has been used to detect dengue and Zika virus single-stranded RNA or mutations in clinical samples, showing great potential for multiplexable, portable, rapid detection of nucleic acids [59]. Recently, they combined RT-RPA technology with the SHERLOCK system (namely CRISPR diagnostics) to detect the S and ORF1ab genes of 2019-nCoV (Figure 4(b) and (c)) [60]. The CRISPR diagnostics-based test can be conducted in 1 hour and can be read using a dipstick. The analysis is performed at 37°C and 42°C, and its detection sensitivity is ten copies per microliter of input, exhibiting unique advantages, such as high sensitivity, specificity, speed, and suitability for point-of-care testing. However, this approach needs to be validated using real patient samples.

Unlike the CRISPR/Cas13a system, the CRISPR/Cas12a system is based on the collateral effect of Cas12a on single-stranded DNA (ssDNA). Chen and colleagues combined Cas12a ssDNase activation with RPA technology to create a new approach, named DNA endonuclease-targeted CRISPR trans reporter (DETECTR), with attomolar sensitivity for DNA detection (Figure 4(a)) [61]. DETECTR was also validated with clinical samples, showing the capacity for rapid, specific detection of human papillomavirus (HPV) [61]. Recently, DETECTR was investigated to identify the nucleic acid of 2019-nCoV. Lucia et al. applied the DETECTR (CRISPR-Cas12a and RT-RPA) to detect the RNA-dependent RNA polymerase (RdRp), ORF1b, and ORF1ab genes of 2019-nCoV using synthetic RNA fragments as samples [62]. Remarkably, all steps of the test were completed in 1 h, and results were visible to the unaided eye. The limit of detection for ORF1ab was ten copies/μL. The advantages of this method are its portability and low cost (~US$2 per reaction). But this proposed approach also needs to be validated with clinical samples before commercialization. Another DETECTR-based 2019-nCoV detection strategy was developed by Chiu’s lab [63]. They employed LAMP, CRISPR/Cas12, and lateral flow assay to detect the E and N genes of 2019-nCoV in clinical samples. This protocol supplied rapid (~30 min), low-cost, and accurate (100% specific vs. 90% specific for qRT-PCR) detection of 2019-nCoV in respiratory swab samples. Realistically, CRISPR/Cas-based 2019-nCoV detection technology is highly specific, rapid, and low cost, but the detection strategy also needs to be validated using clinical samples.

2.1.5. Microfluidic-Based Detection

The abovementioned methods are based on relative quantification, because they require external calibration with genetic standards or inner reference DNA templates, resulting in unavoidable errors and other uncertainties. On the contrary, methods that do not need standard curves can provide a quantitative analysis of nucleic acids using absolute quantification of genetic copies. Recently, digital PCR and digital LAMP have been achieved with microelectromechanical and microfluidic technologies [64, 65].

Microfluidic or lab-on-a-chip techniques use microsized channels to process or manipulate fluids. Microfluidics has been widely utilized in various fields, including drug screening, tissue engineering, disease diagnostics, and nucleic acid detection [66, 67]. Based on its portability and ultralow sample consumption, microfluidics shows significant promises in clinical applications [68]. Regarding nucleic acid analyses, microfluidic devices aliquot diluted nucleic acid samples into hundreds to millions of discrete nanoliter chambers. The isolated chambers contain only one or zero target molecule according to a Poisson distribution. Consequently, the absolute copy number of target nucleic acid can be calculated from the number of positive and negative reactions, based on the Poisson distribution formulas [69, 70]. Both digital PCR and digital LAMP have employed microfluidics for pathogen analysis, which is suitable for COVID-19 detection. For instance, Ottesen and colleagues used digital PCR to amplify and analyze multiple genes on a microfluidic chip [71]. This chip consisted of parallel chambers and micromechanical valves. The micromechanical valves segmented chambers into independent PCR reactors after the sample flowed into chambers through connection channels. The chip was able to detect several kinds of genes with parallel sample panels. Digital PCR can also be conducted with droplets generated by the microfluidic chip. However, the detection of fluorescent signals in droplets requires special instruments, such as flow cytometers, which may limit its application in point-of-care testing. Additionally, the high temperature in PCR amplification tends to evaporate the reaction liquid (nanoliter or even femtoliter), leading to unacceptable errors. Using airtight devices or high pressure delays liquid evaporation but complicates the devices and increases testing costs.

Digital LAMP is more compatible with microfluidics than digital PCR because it is executed at a moderate temperature. This simplifies microfluidic devices and reduces testing costs. Many microfluidic devices have been reported for nucleic acid detection using digital LAMP, such as self-digitization chips, self-priming compartmentalization chips, and droplet-generation chips [7274]. As an example, Xia et al. designed a mathematical model using the Monte Carlo method according to the theories of Poisson statistics and chemometrics [70]. The mathematical model illustrated influential factors of the digital LAMP assay, guiding the design and analysis of digital LAMP devices. Based on the established mathematical model, they fabricated a spiral chip with 1200 chambers (9.6 nL) for pathogen detection (Figure 5(a)–(c)). This spiral chip operated at 65°C without visible liquid evaporation and achieved a quantitative analysis of nucleic acids over four orders of magnitude in concentration with a detection limit of 87 copies per mL. This portable gadget shows significant promise in future point-of-care testing.

Microfluidics, combined with enzyme-DNA nanostructures, is also applied to detecting 2019-nCoV. Ho et al. developed a modular detection platform (termed enVision) consisting of an integrated circuit of enzyme-DNA nanostructures for direct and versatile detection of pathogen nucleic acids from infected cells [75]. Built-in enzymatic cascades in the enVision microfluidic system supply a rapid color readout for detecting HPV. The assay is fast (<2 h), sensitive (), and readily quantified with smartphones. Recently, they adopted the enVision microfluidic system to detect 2019-nCoV [76]. Preliminary results showed that the enVision platform is sensitive, accurate, fast (within 0.5-1 h), and inexpensive (less than $1 per test kit). This novel platform works at room temperature and does not require a heater or special pumps, and it uses a minimal amount of samples, making it highly portable. However, this platform needs to be further validated with real clinical samples.

2.2. Target Antigen and Antibody

As mentioned above, the primary diagnostic methods are virological detection involving viral nucleic acids. Another approach to detection is with serological assays that measure antigens or antibodies present in the host. Such testing provides vital information about host exposure to 2019-nCoV and is useful for detection and surveillance purposes. For instance, this method greatly helps medical professionals to determine whether some recovered patients have a higher risk of reinfection. However, the disadvantage is that one should be cautioned that in the early stages of COVID-19 infection, the host’s antibodies are often not within the detectable range of serological test kits. Besides, there was no proven evidence on the duration of IgM or IgG antibodies circulating in the host after recovery. It could be merely a short time frame for detection. As such, serological tests should not be solely used for COVID-19 diagnosis.

2.2.1. Enzyme-Linked Immunosorbent Assay (ELISA)

Early diagnosis of 2019-nCoV infection is of utmost importance both for medical teams to manage patients effectively and for policymakers to curb the viral spread. Presently, ELISA in cell culture extracts has proven to be the working “gold standard” for laboratory diagnosis of 2019-nCoV [77]. ELISA is a plate-based assessment method for detecting and quantifying biomolecules, including peptides, proteins, antibodies, and hormones. ELISA techniques depend on specific antibodies to bind target antigens and a detection system to indicate the presence of antigen binding. In an ELISA, an antigen must be immobilized to a solid surface and then complexed with an antibody that is linked to an enzyme. Detection is accomplished by assessing the conjugated enzyme activity after incubation with a substrate to produce a measurable product [78]. Recently, coronavirus proteins have been widely used in ELISA to diagnose SARS-CoV or other viruses within the coronavirus family [79].

In a bold, novel approach, a team of infectious disease experts in Singapore utilized an ELISA against 2019-nCoV to ascertain that suspected subjects were infected with COVID-19 and discovered the connection between two COVID-19 clusters in the local community [80]. Using blood samples taken from alleged COVID-19 patients, the researchers detected antibodies targeting the spike protein that prevented the virus from killing cells in laboratory tests. They verified that a couple allegedly infected with COVID-19 had the disease because they had exceedingly elevated levels of virus-specific antibodies in their blood. Interestingly, PCR tests on the couple yielded negative results. Because the couple had recovered from the 2019-nCoV infection, they had no viral genetic materials in their bodies, but the antibodies persisted. There were also other reports of using ELISA to diagnose 2019-nCoV infection [81, 82]. Each study confirmed the high reproducibility and specificity of ELISA in diagnosing COVID-19 patients accurately in clinics.

2.2.2. IgG/IgM Lateral Flow Assay (LFA)

Research has established that the presence of immunoglobulin M (IgM) indicates a primary defense against viral infections. This IgM defense occurs before the production of high-affinity and adaptive immunoglobulin G (IgG) that is critical for prolonged immunity and immunological memory [83]. From a previous study on SARS infections, both IgM and IgG antibodies could be detected in the patient blood after 3-6 days and beyond 8 days, respectively [84]. Given that 2019-nCoV belongs to the same family of coronaviruses including MERS and SARS, 2019-nCoV should also generate IgM and IgG antibodies in infected humans. Therefore, the detection of IgM and IgG antibodies may provide epidemiologists with crucial information on viral infection of test subjects, allowing them to adjust policies to combat the pandemic more effectively.

Point-of-care lateral flow immunoassays are performed qualitatively to quickly determine the presence of 2019-nCoV by detecting anti-2019-nCoV IgM and anti-2019-nCoV IgG antibodies in human plasma, serum, or whole blood. A typical device is shown in Figure 6(a). Reddish-purple lines in the readout indicate the presence of 2019-nCoV IgM and IgG antibodies in the sample. LFA is based on the lateral chromatographic flow of reagents that bind and interact with the sample. As the sample flows through the test device, starting at the sample pad region, the anti-2019-nCoV IgM and IgG antibodies, if present, bind tightly to 2019-nCoV antigen-labeled gold nanoparticles, located on the conjugated pad. When conjugated products in the sample continue to move up the strip, anti-2019-nCoV IgM antibodies and anti-2019-nCoV IgG antibodies bind to anti-human IgM (M line) or anti-human IgG (G line), respectively. No visible lines can be seen when the specimen does not contain anti-2019-nCoV antibodies because no labeled complexes bind at the test zone. IgG-labeled gold colorimetric nanoparticles serve as the control when they bind to anti-rabbit IgG antibodies at the control line (C) (Figure 6(b)). LFA has proven useful in detecting 2019-nCoVIgM/IgG antibodies in clinical studies, demonstrating 88.66% test sensitivity and 90.63% specificity in human blood, serum, and plasma samples. Results from six patients are shown in Figure 6(c). Common 2019-nCoV detection methods are summarized in Table 1.

MethodSampling methodsDetection timeAccuracy/limit of detectionAdvantagesRemarks and Ref.
RapidLow costSensitivePortableVisual analysis

 IgG/IgM-LFABlood15 min92.69%Inapplicable to early-stage detection [243]
 IgG/IgM-AIE-QDBlood15 min75%Inapplicable to early-stage detection [244]
 IgM-colloidal gold-LFABlood15 minNot reportedInapplicable to early-stage detection [245]
 IgG/IgM-ELISA or LFABlood29 min93.1%Inapplicable to early-stage detection [246]
 IgG/IgM-colloidal gold-FLABlood15-30 min90%Inapplicable to early-stage detection&
Nucleic acid (whole genome)
 Nanopore target sequencingThroat swab6-10 h>95%, 10 copies/mLMonitor mutation but time-consuming and costly [28]
Nucleic acid (N and E genes or ORF1ab/RdRp/S)
 Real-time RT-PCRNasopharyngeal or oropharyngeal swab240-360 min67%, 3.2 copies/μLN/AN/AN/AN/AN/AEstablished standard method but time-consuming and requiring skilled personnel&
 RT-LAMPNasopharyngeal or oropharyngeal swab30 min>95%A single, simple protocol but with noisy signals&
 Close-tube Penn-RAMP (LAMP+RPA)Synthetic RNA100 min7 copies per reactionSuitable for home screening but requiring clinical validation [45]
 CepatNasopharyngeal or oropharyngeal swab5-10 min99%High specificity but requiring clinical validation [247]
 CRISPR-Cas12a/RT-LAMP (DETECTR)Nasopharyngeal/oropharyngeal swab45 min10 copies/μL inputRequiring clinical validation [248]
 HTX COVID-19 test kitNasopharyngeal or oropharyngeal swab180 min99%Severity evaluation possible but requiring clinical validation [249]
 enVisionSynthetic RNA30 minNot knownRequiring clinical validation [76]
 CRISPR-Cas13a/RPA-LFA (SHERLOCK)Synthetic RNA<60 min10 copies/μL inputSimple but requiring clinical validation [60]
 CRISPR-Cas12a/RT-RPA (DETECTR)Synthetic RNA<60 min10 copies/μL inputRequiring clinical validation [62]
 Multiparameter-chip/RPASynthetic RNA<60 min>90%Requiring clinical validation [250]

N/A: not available (an established method used for comparison in this table); &: commercial kits; LAMP: loop-mediated isothermal amplification; RPA: recombinase polymerase amplification; FLA: lateral flow assay; CRISPR: clustered regularly interspaced short palindromic repeats; DETECTR: DNA endonuclease-targeted CRISPR trans reporter.
2.3. Supplementary Detection Methods

Various diagnostic techniques have been used to complement RT-PCR and antibody-antigen serological testing. These include chest computed tomography (CT) and transmission electron microscopy (TEM). Each has its place in diagnostic settings and can serve as a complementary diagnostic tool to aid medical investigators in diagnosing 2019-nCoV accurately in suspected COVID-19 patients.

2.3.1. Chest Computed Tomography (CT)

In clinics, medical imaging tools are indispensable and form an essential component of viral diagnosis, as well as for monitoring viral progression [85]. They have also been used for follow-up in outpatient settings for coronavirus-related pulmonary disorders. Just like both SARS and MERS, pulmonary complications in COVID-19 patients have been observed. Learning from the well-documented SARS and MERS studies, CT imaging results in the acute and chronic periods of COVID-19 are invariant, but not always present [8689]. Evidence is found in previous studies on SARS and MERS. The glass opacities observed are not always found in COVID-19 patients. Crucially, preliminary imaging discoveries indicate that COVID-19 yields nonspecific results as well [9092]. Radiologists are presently striving to any characteristics specific to COVID-19, although present medical information remains limited. Given the precarious situation, there is a pressing need for alternative, complementary diagnostics. CT is one example. COVID-19 patients often develop “ground glass” lung opacities [93]. As such, a CT imaging scan can readily identify lung abnormalities in human subjects, thereby enabling early treatment against COVID-19. CT has demonstrated some common imaging characteristics in COVID-19 patients. These features include bilateral, multifocal, ground glass opacities, with a peripheral distribution (Figure 7(a)) [93]. Crucially, more than half of 90 patients under study presented multilobar involvement and lesions more prominently in the lower lobes of their lungs. Given its feasibility and ease of use, CT has become an essential tool for the 2019-nCoV infection diagnosis. From a radiological perspective, the advantages of using CT imaging could expedite the rate of diagnosis. It also supports the current shortage and heavily reliant on technical know-how during RT-PCR testings. Nonetheless, one limitation is that it should be cautiously utilized as a diagnostic approach because there are no proven, evidence-based clinical benefits of using CT. It could also cause false securities if results are negative. Other limitations include requirements of relatively high-dose CT scans and long-term, continuous usage, which can altogether be logistically challenging and deplete additional medical resources.

2.3.2. Transmission Electron Microscopy (TEM)

Transmission electron microscopy (TEM) has been used for many years and has had a profound impact on our understanding of illnesses, including viral infections. The thousandfold enhanced resolution provided by TEM enables investigators to visualize viral morphology and to classify viruses into families [94].

Mechanistically, TEM operates based on interactions between electrons emitted from a source and materials under examination. In the present context, it is usually 2019-nCoV in a cellular sample [95]. The detector collects a multitude of signals from transmitted electrons, before processing them to reveal viral morphology and location within cells [96]. Typical specimen preparation for TEM includes sample fixation, embedding, sectioning, staining, and loading onto the TEM copper grids [94, 97, 98]. 2019-nCoV sampling typically uses supernatants from patient airway epithelial cells. Infected cells are fixed and dehydrated before embedding in resin. A negatively stained, film-coated grid for examination is similarly prepared for contrast enhancement. 2019-nCoV virus particles seen with TEM are shown [97] (Figure 7(b)). TEM enables microbiologists to rapidly diagnose patients with a single examination of a single tissue sample.

3. Medical Treatment

There are three general approaches to develop potential antiviral treatments of the human coronavirus. Firstly, standard assays may be used to evaluate existing broad-spectrum antiviral drugs. Secondly, chemical libraries containing existing compounds or databases may be screened. Thirdly, specific, new medications based on the genome and biophysical understanding of 2019-nCoV can be designed and optimized. Therefore, this section will discuss some of the potential 2019-nCoV therapeutics obtained through these general approaches. Besides chemical and biologic drugs commonly used in antiviral therapies, we further elaborate on how nanomaterials, nutritional interventions, traditional Chinese medicine, and stem cell therapy can be potentially used for treatment or as an adjuvant to reduce the mortality and morbidity rate of 2019-nCoV patients. Finally, to end this section, we highlight vaccines as a key therapeutic option to eradicate COVID-19 through herd immunity without getting the disease.

3.1. Chemical Drugs

There are currently no approved antiviral drugs to treat COVID-19, and patients must depend upon their immune systems to combat the infection. A full-fledged treatment plan has yet to emerge, and both academia and pharmaceutical companies are racing to develop new treatments and vaccines to address COVID-19. Research into the cellular and molecular pathogenesis of 2019-nCoV has provided essential insights with the hope of developing viable therapies. While researchers are working on cures or preventive measures for COVID-19 [99], a more robust, efficient, and economical way to tackle the disease is to repurpose existing drugs into a viable therapeutic strategy. Drug repurposing, also termed drug repositioning, refers to the process of discovering new therapeutic applications for existing drugs. It offers various advantages over traditional de novo drug discovery, i.e., reduced cost and drug development time, established drug characteristics, and, most importantly, established safe dosages for human use [100]. Repurposed drugs often negate the need for phase 1 clinical trials and can be used immediately [100, 101]. At present, repurposed drugs are the only option available at treatment centers for COVID-19 patients. As COVID-19 is a viral infection, the most obvious choices for repurposed drugs come from known antiviral drugs [102]. Antiviral creation strategies focus on two approaches: targeting viruses or targeting host cell factors. In this section, we will review antiviral drugs prescribed or proposed against COVID-19 based on the antiviral drug creation strategies.

3.1.1. Entry Inhibitors

When an infection occurs, the virus gains entry into a host cell by attaching itself to the host cell surface (Figure 8) [103]. This relies on numerous interactions between the virion surface and the specific proteins on the cell membrane. In general, these surface proteins have other functions but are serendipitously recognized by the virus as entry receptors [103]. Molecules that prevent such recognition, either by competitive binding or by downregulating the receptors, are known as viral entry inhibitors (Figure 9(a)). These inhibitors are valuable as therapeutics since blocking infection early in the life cycle reduces cellular and tissue damage associated with viral replication and production of viral progeny.

As mentioned above, coronavirus particles comprise four structural proteins: the S, E, M, and N proteins [104107]. The S protein is the most crucial in viral attachment, fusion, and entry [108]. It comprises two subunits. S1 facilitates attachment to the host cell receptor, while S2 mediates membrane fusion of the virion and the host cell. As mentioned above, viruses have specific attachment sites. SARS-CoV recognizes ACE2 as its host receptor, while MERS-CoV recognizes dipeptidyl peptidase 4 [109, 110]. Like SARS-CoV, 2019-nCoV also targets host ACE2 [111113]. Biophysical and structural analysis indicates that the 2019-nCoV S protein binds ACE2 with higher affinity than the SARS-CoV S protein [16]. Therefore, it is vital to target ACE2 for the development of viral entry inhibitors.

To the best of our knowledge, not much is known about ACE2-specific inhibitors that are commercially available or under commercial development [114]. However, ACE2 stimulators have been used in the treatment of hypertension, cardiac diseases, and diabetes mellitus to regulate the renin-angiotensin system [115, 116]. There are also ACE inhibitors known for treating the diseases mentioned, but these lack inhibitory activity toward ACE2 due to their distinct substrate-binding pockets [116119]. In brief, there are concerns that both ACE2 stimulators and ACE inhibitors can increase the expression of ACE2, which in turn may increase susceptibility to viral host cell entry [120, 121]. Much work needs to be done on ACE2-targeting drugs, and controversial issues that lie beyond the treatment pathway need to be addressed soon.

A small antiviral molecule, umifenovir, has entry inhibitory effects on the influenza virus. Umifenovir targets hemagglutinin for its anti-influenza virus effect [122124]. Hemagglutinin, a viral cell surface protein, facilitates infection by undergoing a conformational change when the virus binds to host cells [122]. Umifenovir interacts with hemagglutinin to stabilize it against low pH-induced conformational change via the formation of an extensive network of noncovalent interactions that prevent hemagglutinin-mediated membrane fusion [122, 124]. It also interacts with phospholipids by altering membrane fluidity [125], which is vital for the fusion process. This is most likely due to umifenovir’s molecular interactions (bearing both the H donor and acceptor groups) with the interfacial region of the lipid bilayer by competing for the hydrogen bonding of phospholipid C=O groups with water molecules [126]. This renders lipid bilayers of host cells less prone to viral fusion [125]. No studies have shown that umifenovir is effective in inhibiting SARS-CoV or 2019-nCoV. Wang et al. reported that 4 patients with mild/severe COVID-19 recovered after prescription of combined lopinavir/ritonavir, arbidol (umifenovir), and Shufeng Jiedu Capsule (a traditional Chinese medicine) [127]. On the other hand, Dong et al. found in an in vitro study that arbidol may effectively inhibit 2019-nCoV infection at a concentration of 10-30 μM [128].

Chloroquine, also a small molecule, is a quinine analog used to prevent and treat malaria. Similar to umifenovir, chloroquine exhibits its inhibitory effect on influenza by pH stabilization. Chloroquine is a weak base and becomes protonated intracellularly in a manner described by the Henderson-Hasselbalch law [129]. It can raise lysosomal pH to facilitate autophagy intracellularly [130132]. Chloroquine also alters the signaling pathway of enzymes, causing enzyme glycosylation, ultimately inhibiting viral replication in host cells [133, 134]. Liu et al. claimed that chloroquine could inhibit SARS-CoV entry by changing glycosylation of the ACE2 receptor and S protein [135]. Chloroquine’s effective inhibition of SARS-CoV was demonstrated in vitro on primate cells and human rectal cells [136, 137]. Hydroxychloroquine is a derivative of chloroquine with an additional hydroxyl group. These two chloroquines share similar structures and mechanisms. Both have shown in vitro antiviral activities toward 2019-nCoV [138140]. Hydroxychloroquine was more effective than chloroquine in inhibiting 2019-nCoV in vitro on primate cells [141]. Until now, chloroquine has shown apparent efficiency and safety against 2019-nCoV in clinical trials conducted in China [139]. Currently, chloroquine or hydroxychloroquine has been administered to hospitalized 2019-nCoV patients on an uncontrolled basis in various countries, including China and the USA [42]. However, it must be noted that chloroquine and hydroxychloroquine cause ocular toxicity [142]. Hydroxychloroquine is reportedly less toxic than chloroquine, making it more attractive as a prescription drug [135, 143]. Nevertheless, more investigation and clinical trials are needed to evaluate further their efficacy and safety in treating 2019-nCoV.

3.1.2. Protease Inhibitors

Proteases are essential enzymes that regulate cell life processes such as cell growth and death, blood clotting, inflammation, fertilization, and infection [103]. Viral entry into host cells requires S protein priming by host proteases, which subsequently enables the fusion of viral and cellular membranes [113]. Membrane fusion enables the release of the viral genome into the host cytoplasm, initiating RNA translation into protein. Most viruses also encode their proteases to protect viral proteins by modulating host cell responses. While proteases are vital for cell life processes, they have become promising targets for antiviral therapeutic agents. Protease inhibitors prevent viral replication by binding selectively to viral proteases or blocking proteolytic cleavage of protein precursors necessary for the production of infectious particles [144]. It is noteworthy that protease inhibitors were a major therapeutic breakthrough of antiviral drug design in the mid-1990s for the treatment of HIV. Most HIV protease inhibitors have found prominent clinical use (Figure 9(b)).

Coronavirus S proteins can be primed by a multitude of proteases [145]. Hoffmann et al. demonstrated that the S protein of 2019-nCoV could be primed by serine protease TMRPSS2 [113]. Similarly, both SARS-CoV and MERS-CoV can be activated by other TMPRSS family members [145]. TMPRSS family proteases are widely expressed in the respiratory tract [145, 146], which is likely the reason that coronaviruses cause acute respiratory distress syndrome. Upon successful priming, the viral genome encoding RNA and several nonstructural proteins, including coronavirus main protease (3CLpro), papain-like protease (PLpro), and RdRp, are released [147149]. The single-stranded positive RNA is translated into viral polyproteins by ribosomes in the host cell cytoplasm. The polyproteins are then cleaved into effector proteins by viral proteases: 3CLpro and PLpro. PLpro also acts as a deubiquitinase that may remove specific host cell proteins (e.g., interferon regulatory factor 3 (IRF3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)), thus weakening the immune system [147, 149, 150]. Both host and viral proteases are essential therapeutic targets in the case of COVID-19.

Camostat mesylate is a small molecule that has shown an excellent therapeutic effect for chronic pancreatitis treatment by targeting proteases [113, 151, 152]. Camostat mesylate primarily inhibits enzymatic autodigestion of the pancreas [153]. In vivo studies on rats with pancreatic fibrosis showed that camostat mesylate inhibits inflammation, cytokine expression, and fibrosis in the pancreas [154]. It has an additional clinical benefit for pancreatic pain by preventing enzyme-evoked activation of pain receptors [155]. As mentioned above, the TMPRSS family, especially TMRPSS2, is most likely the protease targeted by a coronavirus. Camostat mesylate inhibits TMPRSS2 activity on primate cells in vitro, completely blocking membrane fusion between the host cell and the viral MERS-CoV particle [156]. Zhou et al. claimed that camostat mesylate displays an inhibitory effect in mice for SARS-CoV infection [152]. Recent research by Hoffmann et al. showed a promising in vitro inhibitory effect of this serine protease inhibitor in SARS-CoV and 2019-nCoV on human lung cells, showing potential as a viable option for COVID-19 treatment [113]. Unfortunately, in vitro and in vivo data for camostat mesylate against coronaviruses are limited. More investigation is required to evaluate camostat mesylate as a potential therapeutic against COVID-19.

Lopinavir-ritonavir is a coformulated antiretroviral drug with excellent efficacy against HIV-1. The lopinavir has a core molecular structure identical to ritonavir. The 5-thiazolyl end group and 2-isopropylthiazolyl group in ritonavir are replaced by the phenoxyacetyl group and a modified valine, respectively, in which the amino terminus has six-membered cyclic urea attached. In brief, lopinavir is a potent protease inhibitor developed from ritonavir with high specificity for HIV-1 protease [103]. It represents a higher proportion of the coformulation. Lopinavir contains a hydroxyethylene scaffold mimicking a standard peptide bond cleavable by HIV-1 protease [157]. This results in the production of noncontagious viral particles. On the other hand, ritonavir binds to HIV-1 protease, interrupting the maturation and production of viral particles [158]. A clinical study from Hong Kong has shown that the combination of lopinavir-ritonavir and ribavirin treatment for 152 patients against SARS-CoV had an overall favourable clinical response [159]. It has been demonstrated that lopinavir-ritonavir targets 3CLpro of 2019-nCoV and further indicated that 3CLpro might also be the targets of protease inhibitors for other coronaviruses [160]. Regrettably, a recent clinical trial using lopinavir-ritonavir in Wuhan, China, reported that 199 hospitalized adult patients infected with 2019-nCoV did not benefit from the treatment [161]. Given such conflicting clinical data, physicians must carefully weigh lopinavir-ritonavir as a COVID-19 treatment.

Darunavir is another antiretroviral protease inhibitor drug effective against HIV-1. Darunavir is designed for multidrug-resistant HIV-1 protease variants, due to its molecular structure, which introduces more hydrogen bonds compared to conventional antiretroviral medicines. In general, changes in van der Waals and hydrogen bonding interactions between inhibitors and proteases affect the potency of antiretroviral drugs [162]. Aside from enzymatic inhibition, darunavir inhibits protease dimerization [163]. The dimerization of HIV protease is essential for the acquisition of its proteolytic activity for the maturation of viral particles [163]. Lin et al. claimed that darunavir inhibits 2019-nCoV. The group has used molecular modeling to evaluate darunavir binding to 3CLpro and PLpro proteases and found targeted activity against the latter [164]. Nevertheless, the therapeutic effect of darunavir in COVID-19 clinical cases remains untested [164]. This may be in part due to potential side effects, such as liver damage and severe skin rashes [103, 165]. These contraindications must be carefully evaluated if darunavir is to be considered a potential therapeutic agent for COVID-19.

3.1.3. Replication Inhibitors

Polymerases are enzymes essential for viral replication to produce viral progeny. Viral DNA and RNA polymerases are responsible for duplicating the viral genome and facilitating transcription and replication [103]. Replication inhibitors (Figure 9(c)) interfere with the production of viral particles by blocking enzymatic activity, ultimately causing chain termination during viral DNA or RNA replication [166]. There are four types of viral polymerases in viruses: RNA-dependent RNA polymerases, RdRp, DNA-dependent RNA polymerases, and DNA-dependent DNA polymerases.

In the section Protease Inhibitors, we mentioned that RdRp is released upon successful priming. RdRp is a necessary polymerase that catalyzes the replication of RNA from an RNA template for coronaviruses [167]. Release of RdRp from the virus initiates the synthesis of a full negative-strand RNA template to be used by RdRp to replicate more viral genomic RNA, which eventually turns host cells into virus factories [147]. Therefore, RdRp is an attractive therapeutic target to prevent host cells from producing viruses.

Ribavirin is a synthetic guanosine nucleoside analog that mimics purines, including inosine and adenosine, and ribavirin has been used in the treatment of respiratory syncytial virus [168]. It has only one ring at the heterocyclic base, compared with guanine’s two rings. Notably, ribavirin has a ribose sugar moiety with a hydroxyl group at the 2-carbon position, enabling preferential activity in RNA-related metabolism [168, 169]. Ribavirin inhibits cellular enzyme and inosine monophosphate dehydrogenase involved in purine nucleotide biosynthesis [170, 171]. Ribavirin is also known for its inhibitory effect on viruses by forcing viral genome replication to become catastrophically error-prone. It is likely that as a nucleoside analog, ribavirin is incorporated by RdRp into the newly synthesized viral genome, where it induces mutagenesis [170, 172]. Although ribavirin has proven effective against viral infections, its mechanism of action has not been firmly established, and there are several proposed mechanisms of action that require further validation [168, 173]. Ribavirin was initially used in treating SARS; however, ribavirin treatment lacked an in vitro antiviral effect and caused adverse side effects including anemia, hypoxemia, and decreased hemoglobin levels [174]. However, ribavirin was used as the primary treatment during the MERS outbreak [175]. In general, clinical studies of ribavirin treatment for SARS and MERS did not show strong evidence of efficacy against these coronaviruses [176178]. There have been no studies of ribavirin’s efficacy against COVID-19. Therefore, the use of ribavirin remains controversial and requires more investigation for a better understanding of its mechanism of action, efficacy, and toxicity, even though it is a widely available drug.

Favipiravir is a synthetic guanine analog frequently used for influenza treatment [179]. Structurally, favipiravir is closely related to ribavirin, in which it shares the same carboxamide moiety [180]. While ribavirin interacts with the viral polymerase directly, favipiravir must be phosphoribosylated by cellular enzymes to its active form, favipiravir-ribofuranosyl-5-triphosphate (RTP) [181, 182]. The viral polymerase mistakenly recognizes favipiravir-RTP for a purine nucleotide, thereby disrupting viral genome replication [181, 182]. Favipiravir has not been used against SARS and MERS previously, but interestingly, it has been shown to reduce viral infection of 2019-nCoV [138, 183]. In a clinical study involving 80 patients infected with 2019-nCoV, conducted in Shenzhen, China, favipiravir showed better efficacy than lopinavir-ritonavir in terms of disease progression and viral clearance [183]. Another clinical study involving 240 patients with COVID-19 conducted in Hubei Province, China, also demonstrated that those treated with favipiravir had a higher recovery rate compared to those treated with umifenovir (preprint) [184]. More clinical data are needed to validate favipiravir’s efficacy and safety in 2019-nCoV treatment.

Remdesivir is a trial synthetic adenosine analog that has not yet been clinically approved [185]. It was synthesized and developed by Gilead Science in 2017 for Ebola virus infection [186]. Remdesivir needs to be metabolized into its active form, GS-441524, to initiate its activity. The active form of remdesivir inhibits viral RNA polymerase and evades proofreading by viral exonuclease, causing an interruption in viral RNA production [138, 185, 186]. It has been demonstrated that remdesivir is effective against MERS-CoV infection in vivo and 2019-nCoV in vitro [138, 187], showing great potential as a therapeutic agent for 2019-nCoV. The drug is currently being validated in clinical trials [188]. Given that antiviral drugs have previously demonstrated reasonable inhibition of coronaviruses and therapeutic efficacy against coronavirus outbreaks, umifenovir, chloroquine, hydroxychloroquine, lopinavir-ritonavir, and ribavirin have been recommended in the latest guidelines for diagnosis and treatment of COVID-19, updated on 17 February 2020 [189].

Recent studies also demonstrated that some antibiotics potentially inhibit 2019-nCoV replication. Anderson et al. (preprint) recently developed the first bat genome-wide RNA interference (RNAi) and CRISPR libraries and identified MTHFDI as the critical host factor for viral infections [190]. MTHFDI is a trifunctional enzyme involved in the one-carbon (C1) metabolic pathway, participating in the cellular production of purine, dTMP, and methyl groups [191]. Anderson et al. demonstrated that purine synthesis activity of MTHFDI is an essential activity for viral replication, making MTHFDI a potential target for developing antiviral drugs [190]. They further explained that an MTHFD1 inhibitor, carolacton, restricts replication of influenza virus, mumps virus, Melaka virus, Zika virus, and, most importantly, 2019-nCoV [190]. Carolacton is a secondary metabolite derived from the mycobacterium Sorangium cellulosum. It is a macrolide ketocarbonic acid. Carolacton has been studied as an antibacterial compound against biofilms of pathogenic Streptococcus mutans and growth of pathogen Streptococcus pneumoniae [192, 193]. It has no toxic effect against eukaryotic cells [194]. It has recently been identified as a potent inhibitor of MTHFDI, and its mechanism of action is presumably due to the ability of carolacton to bind with MTHFDI [194]. More research is needed to validate the mechanism of action, efficacy, and safety of carolacton as a possible treatment for COVID-19. On the other hand, ivermectin is originally a medication used to treat parasite infestation. It comprises different analogs of avermectin: 22,23-dihydroavermectin B1a and 22,23-dihydroavermectin B1b, at a ratio of 4 : 1 [195]. They are macrolide antibiotics isolated from the fungus Streptomyces avermitilis. It has reportedly stopped HIV-I proliferation by inhibiting interaction of the retroviral integrase protein with adapter protein (importin), responsible for the nuclear protein import cycle [196]. Caly et al. reported that ivermectin successfully inhibited 2019-nCoV in vitro but the mechanism of action is unclear [197]. Since ivermectin is an approved drug, it shows great potential as a therapeutic agent for COVID-19. In vivo work or clinical trials need to be done to confirm its efficacy and safety for treatment against COVID-19. Potential drugs for COVID-19 are summarized in Table 2.

Potential therapeutic agentsTarget of inhibitionIndication/purposesPreliminary studiesApplication for COVID-19
Case studiesRemarks

UmifenovirEntry receptorAntiviral drug on influenza; not yet tested for coronavirusesN/ACompared with favipiravir (see favipiravir)Currently being evaluated in China
Chloroquine, hydroxychloroquineEntry receptorAntiviral drug on malaria; not yet tested for coronavirusesIn vitro antiviral activities against 2019-nCoV on primate cells [135, 138]OngoingCurrently being evaluated in China and the United States
Camostat mesylateHost proteaseAntiviral drug on pancreatic diseases; not yet tested for coronavirusesIn vitro antiviral activities against 2019-nCoV in human lung cancer cells [113]Not knownNone
Lopinavir-ritonavirViral proteaseUsed in combination with ribavirin for SARS and MERSN/A199 hospitalized patients, Wuhan, China (99 lopinavir+ritonavir+100 standard care) [161]Currently being evaluated in China and the United States. However, found to be ineffective based on preliminary findings
DarunavirViral proteaseAntiretroviral drug; not yet tested for coronavirusesN/ANot knownNone
RibavirinGenome replicationUsed in combination with lopinavir-ritonavir for SARS and MERSN/ANot knownCurrently being evaluated in China
FavipiravirGenome replicationAntiviral drug on influenza; not yet tested for coronavirusesN/A240 patients in Hubei province, China (120 favipiravir+120 arbidol) (preprint) [184]Higher recovery rate compared to those treated with umifenovir (arbidol)
RemdesivirGenome replicationThe new antiviral drug initially developed for EbolaIn vitro antiviral activities toward 2019-nCoV on primate cells [138]OngoingUnder clinical trials
CarolactonGenome replicationPotential antibacterial compound against biofilm formation of Streptococcus mutans and growth of Streptococcus pneumoniae [192, 193]In vitro antiviral activities against bat kidney cells [190]Not knownNone
IvermectinGenome replicationAntiparasitic drug (broad-spectrum).In vitro antiviral activities against 2019-nCoV on primate cells [197]Not knownNone

N/A: not available. Note: “coronaviruses” only target SARS-CoV and MERS-CoV.
3.2. Nanodrug Delivery System

Nanomaterials have recently been utilized for the treatment of diseases such as cancer [198200] and various types of infections [201, 202]. The ease of modification of surface properties, large surface area [203], and multivalent interactions with targets [204] imbues nanomaterials with massive potential as highly efficacious COVID-19 therapeutic options. However, to the best of our knowledge, no nanoparticle treatment option has been applied to COVID-19. Nonetheless, results obtained from nanoparticle research against other viruses have shown promising potential. For example, Fujimori et al. utilized a CuI nanoparticle to treat H1N1 influenza through the generation of reactive oxygen species (ROS) that inactivate the virus [205]. Silver nanoparticles also show much promise in treating COVID-19 with their broad antiviral properties against a multitude of viruses, including HIV, hepatitis B virus, herpes simplex virus, respiratory syncytial virus, and monkeypox virus [206]. The broad antiviral properties of silver nanoparticles and the generality of ROS inactivation suggest that these nanoparticles can be utilized therapeutically without any modifications. Nanoparticles could also be used for drug delivery. Recently, Herold and Sander demonstrated the use of pulmonary surfactant-biomimetic nanoparticles to encapsulate a stimulator of interferon gene (STING) agonist, 2,3-cyclic guanosine monophosphate-adenosine monophosphate, as an adjuvant in a variety of influenza vaccines [207]. Using nanoparticles as a delivery agent, immune cells were activated without excessive inflammation in the lung. This could provide a considerable benefit for use in COVID-19 vaccines in the future, but as the field is still relatively new, especially in medicinal applications, safety should remain a key consideration in the adoption of nanoparticles in humans.

3.3. Biologic Drugs

In addition to chemical medicines, another vital form of therapy for COVID-19 may be the use of biologics. Currently, interferon-α2b nebulization of 100,000 to 400,000 IU/kg twice a day for 5 to 7 days is one of the main treatments for COVID-19 in children, and it has demonstrated efficacy in reducing the viral load during early stages of infection [208, 209]. Another promising biologic drug is convalescent plasma, the plasma of patients who have recovered from COVID-19 [210, 211]. Antibodies in the donated plasma could confer temporary, passive immunity against COVID-19, allowing patients time to develop active immunity. Clinical trials are currently ongoing [212, 213], and preliminary results announced from the Chinese hospitals have been promising.

On the other hand, human monoclonal antibodies or their fragments developed in the lab have shown encouraging results as well. Tian et al. confirmed the binding of a human monoclonal antibody CR3022 to the receptor-binding domain (RBD) of 2019-nCoV with high affinity [214], highlighting the therapeutic potential of CR3022 toward COVID-19, though further in vitro and in vivo studies are required before it could be used clinically.

3.4. Nutritional Interventions

Another supportive treatment for COVID-19 involves dietary interventions. Various research studies have shown supplementation of multiple vitamins and minerals such as vitamins A, C, and D and zinc can reduce the severity of respiratory infections [215221]. However, most of these studies targeted children below the age of 5 who were suffering from malnourishment or preexisting diseases. Therefore, vitamin and mineral supplementation may offer more significant benefits to COVID-19 patients in developing countries. Moreover, aggressive supplementation of calories and protein in nutritionally at-risk patients has shown significant benefits in reducing mortality [222]. Using a modified Nutrition Risk in Critically Ill (mNUTRIC) score, Kalaiselvan and coworkers demonstrated that 42.5% of mechanically ventilated patients have high nutritional risks (), accompanied by long intensive care unit (ICU) stays and high mortality rates [223].

An estimated 5% of COVID-19 patients require ICU care, and of these critically ill patients, most need mechanical ventilation [224, 225]. Therefore, nutritional intervention using aggressive calorie and protein supplementation may provide substantial benefits to a significant number of critically ill patients. Evidence of such benefits may be provided by the clinical trial (NCT04274322) that is expected to end in July 2020.

3.5. Traditional Chinese Medicine

Traditional Chinese medicine (TCM) is considered a prospective supplementary treatment of COVID-19, due to its impressive performance in treating SARS in 2003 [226]. First, TCM shows a generalized antiviral effect through direct inhibition of viruses and control of inflammation. For example, Weng et al. reported that the Smabucus Formosana Nakai (a traditional medicinal herb) ethanol stem extract displayed strong anti-HCoV-NL63 activity [227]. Moreover, TCM can alleviate damage induced by inflammatory reactions and immune responses initiated by viral infections. Single and combined Chinese medicines could mitigate the cytokine storm by clearing the heat and toxicity in the body. For instance, TCM approaches were adopted to prevent and treat SARS in 2003 and H1N1 influenza in 2009 [228]. As of February 17, 2020, over 85.2% of total confirmed cases (over 60,000 cases) had been treated with TCM, showing that TCM yields excellent outcomes. Notably, in a trial of 102 cases with mild symptoms, TCM achieved remarkable therapeutic effects, demonstrated by faster clinical symptom disappearance and reduction of fever, shorter disease course, higher cure rate (by 33%), and lower rate of moderate-to-severe cases [229]. To date, the National Health Commission (NHC) of the People’s Republic of China has published seven editions of the guidelines for diagnosis and treatment of COVID-19 [25]. Since the fourth version, a list of TCM prescriptions (including TCM soup and TCM capsules) has been recommended for patients based on the stage of the disease and their symptoms [230].

According to the 7th edition of the guidelines, there are three kinds of TCM prescriptions recommended for different stages of patients: the medical observation period, the clinical treatment period, and critical condition (details in Table 3) [25]. Among TCM recipes, the Qing Fei Pai Du Decoction is strongly recommended for treatment of COVID-19 by the NHC of the People’s Republic of China, because it gave a cure rate of over 90% of COVID-19 patients in a clinical trial involving 701 confirmed cases [231]. Another TCM recipe, Xue Bi Jing Injection is specifically recommended for treating critically ill COVID-19 patients, because it suppresses severe sepsis, according to the China Food and Drug Administration. It also promoted significant improvement in cases of severe community-acquired pneumonia (CAP) [232]. Therefore, TCM could be an alternative prophylactic approach to COVID-19 and a supplementary treatment in combination with western medicine to cure COVID-19.

SymptomsPotential TCMMain ingredients (common names)Active ingredientsPrecaution

Suspected cases
 Fatigue, gastrointestinal discomfortHuo Xiang Zheng Qi Capsule (藿香正气胶囊)Patchouli, Indian buead, areca peel, perilla leaf, dahurian angelica root, tangerine peel, platycodon root, largehead Atractylodes rhizome, magnolia bark, pinellia rhizome, licoriceN/AMay cause an autoimmune response. Allergic individuals are prohibited from the treatment. Patients with diseases, i.e., cardiac diseases, liver diseases, kidney diseases, hypertension, and diabetes, and pregnant women should speak to physicians before the treatment
 Fatigue, feverLian Hua Qing Wen Capsule (连花清瘟胶囊)Forsythia, honeysuckle flower, ephedra, apricot, gypsum, indigowoad root, crown wood-fern, heartleaf houttuynia, patchouli, rhubarb, arctic root, mint, licoriceN/AMay cause an autoimmune response. Not suitable for people with a cold. Not suitable for long-term use. Allergic individuals are prohibited from the treatment. Patients with diseases, i.e., cardiac diseases, liver diseases, kidney diseases, hypertension, and diabetes, and pregnant women should speak to physicians before the treatment
Shu Feng Jie Du Capsule (疏风解毒胶囊)Bushy knotweed root, forsythia, indigowoad root, thorowax root, patrinia, verbena leaf, reed root, licoriceN/AMay cause an autoimmune response, i.e., nausea. Allergic individuals and individuals with allergic constitution are prohibited from the treatment
Jin Hua Qing Gan Pill (金花清感丸)Honeysuckle flower, gypsum, ephedra, apricot, baical skullcap root, forsythia, fritillaria bulb, anemarrhena rhizome, great burdock achene, wormwood mint, licoriceN/ASide effects are not known. Pregnant women, allergic individuals, and individuals with allergic constitution are prohibited from the treatment
Confirmed cases
 Mild/general/severeQing Fei Pai Du Decoction (清肺排毒汤)Ephedra, licorice, apricot, gypsum, cinnamon twig, water plantain rhizome, polyporus, largehead Atractylodes rhizome, Indian buead, thorowax root, baical skullcap root, pinellia rhizome, ginger, tatarian aster root, coltsfoot flower, blackberry lily rhizome, Manchurian wildginger, Chinese yam, immature bitter orange, tangerine peel, patchouliN/ANot recommended to be used as a precautionary measure
 SevereXi Yan Ping Injection (喜炎平注射液)AndrographisAndrographolideMay cause adverse reactions, i.e., skin rash, itchiness, fever, pain, dyspnea, cyanosis, palpitations, and convulsions. Pregnant women and allergic individuals are prohibited from the treatment
Xing Nao Jing Injection (醒脑静注射液)Musk, borneol, cape jasmine fruit, turmeric tuberN/AMay cause an autoimmune response, i.e., skin rash. Pregnant women are prohibited from the treatment
 Severe/criticalXue Bi Jing Injection (血必净注射液)Safflower, peony root, Szechuan lovage rhizome, red sage root, Chinese angelica rootHydroxysafflor yellow AMay cause an autoimmune response, i.e., itchiness. Pregnant women are prohibited from the treatment
Re Du Ning Injection (热毒宁注射液)Wormwood, honeysuckle flower, cape jasmine fruitN/AMay cause an autoimmune response, i.e., dizziness, chest tightness, thirstiness, diarrhea, nausea, vomit, skin rash, and itchiness. Allergic individuals are prohibited from the treatment
Tan Re Qing Injection (痰热清注射液)Baical skullcap root, bear bile, goat horn, honeysuckle flower, forsythiaN/AMay cause an autoimmune response, i.e., dizziness, nausea, vomit, itchiness, and skin rash
 CriticalShen Fu Injection (参附注射液)Red ginseng, Chinese aconiteN/AMay cause an autoimmune response, i.e., tachycardia, skin rash, dizziness, headache, hiccup, tremor, dyspnea, nausea, visual abnormality, abnormality in liver function, and urinary retention. Newborns, allergic individuals, and individuals with allergic constitution are prohibited from the treatment
Sheng Mai Injection (生脉注射液)Red ginseng, Ophiopogon, magnolia berryN/AMay cause an autoimmune response, i.e., anaphylactic shock. Newborns, pregnant women, allergic individuals, and individuals with allergic constitution are prohibited from the treatment
Shen Mai Injection (参麦注射液)Red ginseng, OphiopogonN/AMay cause autoimmune response and adverse effect on treated patients, i.e., anaphylactic shock and damage to the body systems. Newborns, pregnant women, allergic individuals, and individuals with allergic constitution are prohibited from the treatment
Su He Xiang Pill (苏合香丸)Storax, benzoin, borneol, musk, buffalo horn, sandalwood, agarwood, clove, nut grass, costus root, frankincense, long pepper fruit, largehead Atractylodes rhizome, gall nut, CinnabarisN/ASide effects are not known. Pregnant women are prohibited from the treatment
An Gong Niu Huang Pill (安宫牛黄丸)Buffalo horn, musk, pearl, realgar, coptis root, Cinnabaris, baical skullcap root, cape jasmine fruit, turmeric tuber, borneolN/AMay cause autoimmune responses, i.e., hypothermia. Prescription guidance is unclear

N/A: not available.
3.6. Stem Cell Therapy

Stem cell therapy is a promising treatment strategy for degenerative diseases, including Huntington’s disease, Parkinson’s and Alzheimer’s diseases, and chronic diseases such as cardiac failure and diabetes [233]. A clinical study showed that transplantation of mesenchymal stem cells (MSCs) significantly lowered the mortality of patients with H7N9-induced acute respiratory distress syndrome (ARDS), with no harmful effects [234]. As H7N9 and 2019-nCoV share similar genome structures and corresponding infection mechanisms, as well as related clinical symptoms (lung failure), MSC-based therapy could be a possible alternative for treating COVID-19. Currently, stem cell-based therapy for COVID-19 is being conducted by different hospitals in China. Doctors from Baoshan Hospital (Yunnan province, China) used human umbilical cord mesenchymal stem cells (hUCMSCs) to treat a 65-year-old critically ill woman with COVID-19. Two days after the 3rd injections of stem cells, the woman recovered, and the throat swab test for COVID-19 turned negative [235]. Another clinical trial involving stem cell therapy was conducted in seven confirmed COVID-19 patients in different clinical stages in Beijing Youan Hospital (Beijing, China). Two to four days after intravenous transplantation of CE2- MSCs, all symptoms such as high fever, weakness, and shortness of breath disappeared in all seven patients without observed adverse effects, indicating that MSCs can cure or significantly improve functional outcomes [236]. There are at least 12 other trials using stem cells to treat COVID-19 in China, according to the WHO report.

3.7. Other Treatments

Vaccines are another promising treatment to prevent or cure specific viruses. Currently, there is no effective vaccine against 2019-nCoV. Fortunately, two COVID-19 vaccines are undergoing clinical trials. The first is Moderna’s mRNA-1273, an mRNA vaccine, which started at KPWHRI in Seattle, USA, on March 16, 2020 [237]. It targets the spike protein of 2019-nCoV. The other vaccine, Ad5-nCoV (a recombinant novel coronavirus disease vaccine (adenovirus type 5 vector)), was conducted at Tongji Hospital in Wuhan, China, on March 16, 2020 [238]. The trial was jointly developed and administered by CanSino Biologics Inc. and the Academy of Military Medical Sciences. Ad5-nCoV, a genetically engineered vaccine, expresses the 2019-nCoV S protein using replication-defective adenovirus type 5 as an expression vector, thereby inducing a virus-specific immune response to prevent COVID-19. There are also several other types of COVID-19 vaccines, including deoptimized live attenuated vaccines, protein vaccine, DNA vaccine, RNA vaccine, and subunit vaccine, all of which are in the preclinical stage (Table 4) [239]. Notably, there is a new microneedle array (MNA) approach based on delivering coronavirus S1 subunit vaccines against COVID-19. Expedited by prior experience in developing vaccines against MERS, this approach was developed within 4 weeks and enabled long-term induction of potent virus-specific antibody responses. Significantly, the MNA work can be extended to other emerging infectious diseases. However, these will require further clinical studies for efficacy and safety, which requires more time.

Vaccine nameVaccine type/platformDeveloperVaccine nameVaccine type/platformDeveloper

Ad5-nCoVDNA/adenovirus type 5 vectorCanSino Biological Inc., Beijing Institute of BiotechnologyVaxil Bio COVID-19 vaccineProtein subunit/signal peptide combinationsVaxil Bio
INO-4800DNA/DNA plasmid, electroporation deviceInovio PharmaceuticalsCOVID-19S-TrimerProtein subunit/pandemic adjuvant systemClover Biopharmaceuticals Inc./GSK
N/ADNA/S geneTakis/Applied DNA Sciences/EvvivaxN/AProtein subunit/S proteinAJ Vaccine
N/ADNA plasmidZydus CadilaN/AProtein subunit/li-Key peptideGenerex/EpiVax
N/AAd26/MVA boostJanssen Pharmaceutical CompaniesN/AProtein subunit/S proteinEpiVax/Univ. of Georgia
GV-MVA-VLP/vaccineDNA/nonreplicating viral vectorGeoVax/BravoVaxProtein subunit/S protein (baculovirus production)Sanofi Pasteur
ChAdOx-nCoV-19DNA/nonreplicating viral vectorUniversity of OxfordN/AProtein subunit/Full-length protein
Matrix-MTM adjuvant
N/ADNA/nonreplicating viral vector, NasoVAX-S geneAltimmuneHeat’s gp96 based vaccine for COVID-19Protein subunit/Heat’s gp96 backbone to express antigen of COVID-19Heat Biologics/Univ. of Miami
N/ADNA/nonreplicating viral vector (Ad5 S)GreffexN/AProtein subunit/molecular clamp stabilized spike proteinUniversity of Queensland/GSK
N/ADNA/nonreplicating viral vector (VAAST); oral vaccine platformVaxart, Inc.N/AProtein subunit/molecular clamp stabilized spike proteinUniversity of Queensland/GSK
N/ADNA vaccine/measles vector (replicating viral vector)Vaxart, Inc.N/AProtein subunit/S1 or RBD proteinBaylor College of Medicine
N/ADNA vaccine/measles vectorInstitute Pasteur/Themis/Univ. of Pittsburg Center for Vaccine ResearchN/AProtein subunit/plant-based coronavirusiBio/CC-Pharming
TNX-1800/COVID-19DNA vaccine/horsepox vaccine platform-S geneTonix Pharma/Southern ResearchN/AProtein subunit/proteinVIDO-InterVac, University of Saskatchewan
mRNA-1273mRNA/novel lipid nanoparticleModerna/NIAIDN/AProtein subunit/proteinUniversity of Saskatchewan
N/AmRNA vaccine/VLP-cocktail (S, M, E, N)/lipid nanoparticleFudan University/Shanghai JiaoTong University/RNACure BiopharmaLive attenuated virusDeoptimized live attenuated vaccinesCodagenix/Serum Institute of India
N/AmRNA vaccine/lipid nanoparticle/S and S-RBD antigenFudan University/Shanghai JiaoTong University/RNACure BiopharmaVLP VaccinePlant-derived VLP/four structural of rotavirus (VP2, VP4, VP6, and VP7)Medicago Inc.
N/AmRNAvaccine/LUNAR®-nanoparticle nonviral delivery systemArcturus/Duke-NUSInactivated VaccineFormalin-inactivated+alum adjuvantedSinovac
BNT162mRNA vaccineBioNTech/Fosun Pharma/PfizerN/AUnknownUniversity of Hong Kong
N/ASelf-amplifying RNA vaccineImperial College LondonN/AUnknown/IPA’s proprietary discovery platformsImmunoPrecise
N/AmRNACureVacN/AUnknownMIGAL Galilee Research Institute
N/AProtein subunit/Drosophila S2 insect cell expression system VLPsExpreS2ionN/AUnknownDoherty Institute
N/AProtein/S proteinWRAIR/USAMRIIDN/AUnknownTulane University

In clinical studies. Preparing for clinical studies. N/A: not available.

According to the 7th edition of the diagnostic criteria [25], patients severely or critically ill with COVID-19 should receive comprehensive antiviral treatment, including lopinavir/ritonavir, arbidol, or Shufeng Jiedu Capsule. Meanwhile, they also need additional treatments, according to their symptoms, including respiratory support (oxygen therapy, high-flow nasal cannulas, or noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation- (ECMO-) based therapy), circulatory support, or continuous renal replacement therapy. The main therapeutic approaches proposed for COVID-19 are summarized in Table 5.

Drug namesOriginal indicationMechanism of actionClinical statusReferences

Chemical drugs
 UmifenovirInfluenza A & BInhibition of binding of the virus to host cell membranePhase 4 trials for COVID-19[122124]
 Chloroquine and derivativesMalariaInhibition of lysosomal activity and signaling pathway in virusPhase 2-3 trials for prophylaxis of COVID-19
Phase 2-4 trials for the treatment of COVID-19
 LopinavirHIVProposed inhibition of 3CLproPhase 2-4 trials for the treatment of COVID-19[159, 160]
 RitonavirHIVProposed inhibition of 3CLproPhase 2-4 trials for the treatment of COVID-19[159, 160]
 DarunavirHIVInhibition of viral maturation pathwaysPhase 2-3 trials for the treatment of pneumonia caused by COVID-19[164]
 Camostat mesylatePancreatic inflammationInhibition of viral entry into host cellsPreclinical[113, 151, 152]
 RemdesivirEbola (proposed)Inhibits viral RNA polymerasePhase 3 trials for the treatment of COVID-19[186, 188]
 FavipiravirInfluenzaInhibits RdRpPhase 3 and randomized trials for the treatment of COVID-19[138, 179182]
 RibavirinHCV, RSVInhibition of viral RNA replication & increased mutation in viral RNAPhase 2 trials for the treatment of COVID-19[168172]
 INF-αHCV, HCL, melanomaInvoking interferon response through exogenous interferonsMultiple randomized trials for COVID-19 patients[208, 209]
 Convalescent plasmaInfluenza, Ebola, SARS, MERSSuppression of viremiaMultiple randomized trials for COVID-19[212, 213]
 Human monoclonal antibodiesNilBinding to the receptor-binding domain of COVID-2019Preclinical[214]
 mRNA-1273, Ad5-nCoVNilEliciting immune response via host cell-expressed viral proteinPhase 1 clinical trials for prevention of COVID-19 infection[237, 238]
 B & T cell epitopesSARS-CoVInvoke immune targeting of these epitopesPreclinical[251]
 MSCHeart disease, Parkinson’s disease, lung cancer, type 1 diabetes, strokePromotes endothelial repair and reduce inflammation through secretion of soluble paracrine factorsPhase 0-1 trials for the treatment of COVID-19[235, 236]
TCM/herbal remedies
 Lian Hua Qing Wen CapsuleInfluenzaDownregulates MCP-1 which decreases monocytes chemotaxis to infection fociPhase 4 trials for the treatment of COVID-19[25, 252]
 Xue Bi Jing InjectionInflammationInhibition of proinflammatory Th17 cells and reduced inflammatory cytokines TNF-α and IL-6Phase 0-4 trials for the treatment of COVID-19[25, 232, 253]
 Re Du Ning InjectionURTISuppressing secretion of inflammatory mediatorsPhase 0 trial for the treatment of COVID-19[25, 254]
 Xi Yan Ping InjectionHFMD, URTIInhibition of NF-κB and MAPK-mediated inflammatory responsesPhase 0 trial for the treatment of COVID-19[25, 255]
 Tan Re Qing Injection/CapsuleURTI, COPDInhibition of NF-κB and MAPK-mediated inflammatory responsesPhase 0-4 trials for the treatment of COVID-19[25, 256]
 Shen Fu InjectionCongestive heart failure, ischemic strokeAffect various immune signaling pathways to have a protective effect against organ damagePhase 4 trial for the treatment of COVID-19[25, 257]

Abbreviations: 3CLpro: 3C-like protease; COPD: chronic obstructive pulmonary disease; HCL: hairy cell leukemia; HCV: hepatitis C virus; HFMD: hand, foot, and mouth disease; HIV: human immunodeficiency virus; IL-6: interleukin 6; INF-α: interferon-alpha; MAPK: mitogen-activated protein kinase; MCP-1: monocyte chemoattractant protein-1; MERS-CoV: Middle East respiratory syndrome-coronavirus; MSC: mesenchymal stem cell; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; RdRp: RNA-dependent RNA polymerase; RNA: ribonucleic acid; RSV: respiratory syncytial virus; SARS-CoV: severe acute respiratory syndrome-coronavirus; Th17: T helper 17; TNF-α: tumor necrosis factor-alpha; URTI: upper respiratory tract infection.

4. Control and Prevention of COVID-19

As the most recent pandemic, COVID-19 induces much fear. It is highly infectious and is transmitted asymptomatically. As such, our best options to slow and prevent transmission are to understand the origin of 2019-nCoV, its transmission route, and associated disease pathways and systems. Generally, a pathogen must remain viable outside the host to allow for environmental spread [240]. Collective effects of many biotic and abiotic factors determine the period that the pathogen can survive [240]. As of now, COVID-19 is thought to be transmitted directly from person-to-person through liquid (droplets) and, more importantly, transmitted indirectly via contact with contaminated surfaces. 2019-nCoV remains viable for a fairly long period outside the human body (up to 72 hours) and is more stable on plastic and stainless steel than on copper and cardboard [241]. Therefore, aerosol and fomite transmission of 2019-nCoV is possible, as the virus lingers among particles or fibers, in airborne liquid droplets, and on surfaces, in some cases for days [241]. Although there are currently insufficient data on the inactivation of environmental 2019-nCoV, data from other coronaviruses can be used as a reference. However, it should be noted that biocidal agents may only limit the survival of coronavirus in critical environments and have no efficacy for infected patients.

Given the high transmissibility of COVID-19, its propensity for asymptomatic transmission, and its persistent nature, confirmed patients could only be quarantined and treated in adequately equipped facilities. This also applies to anyone who has come into contact with these patients. As such, contact tracing is still a mainstay for disease control. Confirmation can be achieved only when specific diagnostic methods have been employed. Chest CT imaging is useful as an initial evaluation for COVID-19, as CT confirmation is often possible even before symptoms appear; therefore, it is recommended for suspected COVID-19 cases [242]. Once the primary diagnosis reveals abnormal chest CT findings, a nucleic acid test should be performed to confirm whether a patient is infected. Once a person is confirmed positive, tests such as C-reactive protein (CRP), complete blood count, urinalysis, biochemical indicators (i.e., liver enzymes, myocardial enzymes, and renal function), blood coagulation function, arterial blood gas analysis, and cytokine levels should be performed to monitor the patient’s condition [189]. Chest CT should be performed as a follow-up to treatment as well [242]. The currently adopted procedure in identifying potential COVID-19 cases in China is summarized in Figure 10.

On a community scale and beyond, strict controls over human traffic are essential to limiting disease transmission. By establishing lockdowns, China has been able to bring the crisis under control. Other nations are now following the Chinese’s approach in restricting movement of residents within their borders. As evidenced globally, social distancing is essential to halt the spread of COVID-19. On the other hand, individuals have the responsibilities to follow the guidelines given by the authorities, to practice good hygiene, and to behave responsibly. COVID-19, like the past epidemics, does not recognize political boundaries, ethnicity, or gender. The disease has challenged the economic and medical infrastructure of the entire globe. As evidenced by events of the past few months, the impact of the outbreak depends upon how well we are prepared to face such a challenge. Only with time will we be able to fully evaluate the measures that are being taken against COVID-19 today.

5. Conclusions

Previous coronavirus epidemics like SARS and MERS have expedited the process of finding useful diagnostic and therapies against 2019-nCoV. It is of paramount importance for all countries to share essential information about 2019-nCoV to mitigate its spread. Because of this strategic approach, research has been mobilized to rapidly develop diagnostic methods and worldwide implementation to minimize the impact of the pandemic. Practical diagnostic tests have aided management and contact tracing of COVID-19 cases in hotspot areas. In this regard, molecular virological techniques have assisted the scientific community in characterizing infectious agents for years. These include qRT-PCR, isothermal amplification, and CRISPR technology.

On the other hand, serological assays for antibodies and antigens present essential tools to obtain valuable information about prior exposure to 2019-nCoV and the prevalence of infection. These include ELISA and LFA technologies. Serological screening also enables novel vaccines to be assessed and supports the design of functional vaccine approaches. Other approaches, including chest computed tomography (CT) and transmission electron microscopy (TEM), can boost existing detection approaches. Notably, there has been a marked increase in the use of both CT and TEM to detect 2019-nCoV and other coronaviruses. These complimentary tools reveal the progression of suspected infection, which cannot be accomplished by conventional diagnostic means. Nonetheless, there is a pressing need for continuous development of rapid, accurate diagnostic devices and strategies to characterize unknown respiratory pathogens.

Despite these signs of progress, the present data suggest that current public health policies and improved diagnostic measures alone may not be sufficient to eradicate COVID-19 in the short term. Efficacious and novel treatments are desperately required. Presently, large numbers of ongoing clinical trials of various drugs may succeed in minimizing morbidity and mortality. We have highlighted several of them in this review. Some are highly promising, while others may require more time to demonstrate usefulness. While some drug candidates appear promising and have been used in treating COVID-19 patients in desperation, it does not necessarily mean that they are proven safe and efficacious in the long run. As such, stringent criteria must be established by health regulatory agencies. However, in the long term, vaccines and prophylactics may be required to curb the spread of 2019-nCoV.

Conflicts of Interest

The authors declare no conflicts of interest.


This work was supported by the Singapore Ministry of Education (MOE2017-T2-2-110); Agency for Science, Technology and Research (ASTAR) (A1883c0011 and A1983c0038); National Research Foundation, Prime Minister’s Office, Singapore, under the NRF Investigatorship programme (Award No. NRF-NRFI05-2019-0003); and National Natural Science Foundation of China (21771135).


  1. WHO, Coronavirus disease (COVID-19) outbreak situation, 2020,
  2. WHO, 2019-nCoV outbreak is an emergency of international concern, 2020,
  3. WHO, WHO Director-General's opening remarks at the media briefing on COVID-19, 2020,
  4. P. C. Woo, S. K. Lau, C. C. Yip, Y. Huang, and K. Y. Yuen, “More and more coronaviruses: human coronavirus HKU1,” Viruses, vol. 1, no. 1, pp. 57–71, 2009. View at: Publisher Site | Google Scholar
  5. P. C. Woo, S. K. Lau, C. S. Lam et al., “Discovery of seven novel Mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus,” Journal of Virology, vol. 86, no. 7, pp. 3995–4008, 2012. View at: Publisher Site | Google Scholar
  6. P. C. Y. Woo, S. K. P. Lau, C. M. Chu et al., “Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia,” Journal of Virology, vol. 79, no. 2, pp. 884–895, 2005. View at: Publisher Site | Google Scholar
  7. J. Peiris, S. T. Lai, L. L. Poon et al., “Coronavirus as a possible cause of severe acute respiratory syndrome,” The Lancet, vol. 361, no. 9366, pp. 1319–1325, 2003. View at: Publisher Site | Google Scholar
  8. N. Zhu, D. Zhang, W. Wang et al., “A novel coronavirus from patients with pneumonia in China, 2019,” The New England Journal of Medicine, vol. 382, no. 8, pp. 727–733, 2020. View at: Publisher Site | Google Scholar
  9. L. E. Gralinski and V. D. Menachery, “Return of the coronavirus: 2019-nCoV,” Viruses, vol. 12, no. 2, p. 135, 2020. View at: Publisher Site | Google Scholar
  10. P. Zhou, X. L. Yang, X. G. Wang et al., “A pneumonia outbreak associated with a new coronavirus of probable bat origin,” Nature, vol. 579, no. 7798, pp. 270–273, 2020. View at: Publisher Site | Google Scholar
  11. A. Wu, Y. Peng, B. Huang et al., “Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China,” Cell Host & Microbe, vol. 27, no. 3, pp. 325–328, 2020. View at: Publisher Site | Google Scholar
  12. J. F.-W. Chan, K. H. Kok, Z. Zhu et al., “Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan,” Emerging Microbes & Infections, vol. 9, no. 1, pp. 221–236, 2020. View at: Publisher Site | Google Scholar
  13. Y. Chen, Q. Liu, and D. Guo, “Emerging coronaviruses: genome structure, replication, and pathogenesis,” Journal of Medical Virology, vol. 92, no. 4, pp. 418–423, 2020. View at: Publisher Site | Google Scholar
  14. J. Wang, S. Zhao, M. Liu et al., ACE2 expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism, medRxiv, 2020. View at: Publisher Site
  15. X. Zou, K. Chen, J. Zou, P. Han, J. Hao, and Z. Han, “Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection,” Frontiers of Medicine, vol. 14, pp. 185–192, 2020. View at: Publisher Site | Google Scholar
  16. D. Wrapp, N. Wang, K. S. Corbett et al., “Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation,” Science, vol. 367, no. 6483, pp. 1260–1263, 2020. View at: Publisher Site | Google Scholar
  17. R. Yan, Y. Zhang, Y. Li, L. Xia, Y. Guo, and Q. Zhou, “Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2,” Science, vol. 367, no. 6485, pp. 1444–1448, 2020. View at: Publisher Site | Google Scholar
  18. K. Wang, W. Chen, Y.-S. Zhou et al., SARS-CoV-2 invades host cells via a novel route: CD147-spike protein, bioRxiv, 2020.
  19. P. Venkatagopalan, S. M. Daskalova, L. A. Lopez, K. A. Dolezal, and B. G. Hogue, “Coronavirus envelope (E) protein remains at the site of assembly,” Virology, vol. 478, pp. 75–85, 2015. View at: Publisher Site | Google Scholar
  20. J. L. Nieto-Torres, M. L. DeDiego, E. Álvarez et al., “Subcellular location and topology of severe acute respiratory syndrome coronavirus envelope protein,” Virology, vol. 415, no. 2, pp. 69–82, 2011. View at: Publisher Site | Google Scholar
  21. T. R. Ruch and C. E. Machamer, “A single polar residue and distinct membrane topologies impact the function of the infectious bronchitis coronavirus E protein,” PLoS Pathogens, vol. 8, no. 5, article e1002674, 2012. View at: Publisher Site | Google Scholar
  22. M. I. Abdelmageed, A. H. Abdelmoneim, M. I. Mustafa et al., Design of multi epitope-based peptide vaccine against E protein of human 2019-nCoV: an immunoinformatics approach, BioRxiv, 2020. View at: Publisher Site
  23. WHO, Report of the WHO-China joint mission on coronavirus disease 2019 (COVID-19), 2020,
  24. V. Surveillances, “The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19)-China, 2020,” China CDC Weekly, vol. 2, pp. 113–122, 2020. View at: Google Scholar
  25. National Health Committee of the People's Republic of China, Diagnosis and treatment guidelines for COVID-19, April 2020,
  26. E. J. Strobel, A. M. Yu, and J. B. Lucks, “High-throughput determination of RNA structures,” Nature Reviews Genetics, vol. 19, no. 10, pp. 615–634, 2018. View at: Publisher Site | Google Scholar
  27. F. Sanger, S. Nicklen, and A. R. Coulson, “DNA sequencing with chain-terminating inhibitors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 74, no. 12, pp. 5463–5467, 1977. View at: Publisher Site | Google Scholar
  28. M. Wang, A. Fu, B. Hu et al., Nanopore target sequencing for accurate and comprehensive detection of SARS-CoV-2 and other respiratory viruses, MedRxiv, 2020. View at: Publisher Site
  29. S. Wei, Z. R. Weiss, and Z. Williams, “Rapid multiplex small DNA sequencing on the MinION nanopore sequencing platform,” G3: Genes, Genomes, Genetics, vol. 8, no. 5, pp. 1649–1657, 2018. View at: Publisher Site | Google Scholar
  30. R. H. Nilsson, S. Anslan, M. Bahram, C. Wurzbacher, P. Baldrian, and L. Tedersoo, “Mycobiome diversity: high-throughput sequencing and identification of fungi,” Nature Reviews Microbiology, vol. 17, no. 2, pp. 95–109, 2019. View at: Publisher Site | Google Scholar
  31. M. Shen, Y. Zhou, J. Ye et al., “Recent advances and perspectives of nucleic acid detection for coronavirus,” Journal of Pharmaceutical Analysis, vol. 10, no. 2, pp. 97–101, 2020. View at: Publisher Site | Google Scholar
  32. A. Tahamtan and A. Ardebili, “Real-time RT-PCR in COVID-19 detection: issues affecting the results,” Expert Review of Molecular Diagnostics, vol. 20, no. 5, pp. 453-454, 2020. View at: Publisher Site | Google Scholar
  33. T. Nolan, R. E. Hands, and S. A. Bustin, “Quantification of mRNA using real-time RT-PCR,” Nature Protocols, vol. 1, no. 3, pp. 1559–1582, 2006. View at: Publisher Site | Google Scholar
  34. Roche's cobas, SARS-CoV-2 test to detect novel coronavirus receives FDA Emergency Use Authorization and is available in markets accepting the CE mark, 2020,
  35. P. Gill and A. Ghaemi, “Nucleic acid isothermal amplification technologies—a review,” Nucleosides, Nucleotides and Nucleic Acids, vol. 27, no. 3, pp. 224–243, 2008. View at: Publisher Site | Google Scholar
  36. P. Craw and W. Balachandran, “Isothermal nucleic acid amplification technologies for point-of-care diagnostics: a critical review,” Lab on a Chip, vol. 12, no. 14, pp. 2469–2486, 2012. View at: Publisher Site | Google Scholar
  37. Y. Mori and T. Notomi, “Loop-mediated isothermal amplification (LAMP): a rapid, accurate, and cost- effective diagnostic method for infectious diseases,” Journal of Infection and Chemotherapy, vol. 15, no. 2, pp. 62–69, 2009. View at: Publisher Site | Google Scholar
  38. C. Li, Q. Ying, X. Su, and T. Li, “Development and application of reverse transcription loop-mediated isothermal amplification for detecting live Shewanella putrefaciens in preserved fish sample,” Journal of Food Science, vol. 77, no. 4, pp. M226–M230, 2012. View at: Publisher Site | Google Scholar
  39. J. H. Kim, M. Kang, E. Park, D. R. Chung, J. Kim, and E. S. Hwang, “A simple and multiplex loop-mediated isothermal amplification (LAMP) assay for rapid detection of SARS-CoV,” BioChip Journal, vol. 13, no. 4, pp. 341–351, 2019. View at: Publisher Site | Google Scholar
  40. P. Huang, H. Wang, Z. Cao et al., “A rapid and specific assay for the detection of MERS-CoV,” Frontiers in Microbiology, vol. 9, p. 1101, 2018. View at: Publisher Site | Google Scholar
  41. K. Pyrc, A. Milewska, and J. Potempa, “Development of loop-mediated isothermal amplification assay for detection of human coronavirus-NL63,” Journal of Virological Methods, vol. 175, no. 1, pp. 133–136, 2011. View at: Publisher Site | Google Scholar
  42. L. Yu, S. Wu, X. Hao et al., Rapid colorimetric detection of COVID-19 coronavirus using a reverse tran-scriptional loop-mediated isothermal amplification (RT-LAMP) diagnostic plat-form: iLACO, MedRxiv, 2020. View at: Publisher Site
  43. G.-S. Park, K. Ku, S. H. Baek et al., “Development of Reverse Transcription Loop-Mediated Isothermal Amplification Assays Targeting Severe Acute Respiratory Syndrome Coronavirus 2,” The Journal of Molecular Diagnostics, 2020. View at: Publisher Site | Google Scholar
  44. W. Yang, X. Dang, Q. Wang et al., Rapid detection of SARS-CoV-2 using reverse transcription RT-LAMP method, MedRxiv, 2020. View at: Publisher Site
  45. M. El-Tholoth, H. H. Bau, and J. Song, A Single and Two-Stage, Closed-Tube, Molecular test for the 2019 novel coronavirus (COVID-19) at home, clinic, and points of entry, ChemRxiv, 2020. View at: Publisher Site
  46. B. Babu, F. M. Ochoa-Corona, and M. L. Paret, “Recombinase polymerase amplification applied to plant virus detection and potential implications,” Analytical Biochemistry, vol. 546, pp. 72–77, 2018. View at: Publisher Site | Google Scholar
  47. I. M. Lobato and C. K. O'Sullivan, “Recombinase polymerase amplification: basics, applications and recent advances,” Trac Trends in Analytical Chemistry, vol. 98, pp. 19–35, 2018. View at: Publisher Site | Google Scholar
  48. A. A. el Wahed, A. el-Deeb, M. el-Tholoth et al., “A portable reverse transcription recombinase polymerase amplification assay for rapid detection of foot-and-mouth disease virus,” PLoS One, vol. 8, no. 8, article e71642, 2013. View at: Publisher Site | Google Scholar
  49. D. S. Boyle, D. A. Lehman, L. Lillis et al., “Rapid detection of HIV-1 proviral DNA for early infant diagnosis using recombinase polymerase amplification,” MBio, vol. 4, no. 2, 2013. View at: Publisher Site | Google Scholar
  50. H. M. Amer, A. Abd el Wahed, M. A. Shalaby, F. N. Almajhdi, F. T. Hufert, and M. Weidmann, “A new approach for diagnosis of bovine coronavirus using a reverse transcription recombinase polymerase amplification assay,” Journal of Virological Methods, vol. 193, no. 2, pp. 337–340, 2013. View at: Publisher Site | Google Scholar
  51. A. A. El Wahed, P. Patel, D. Heidenreich, F. T. Hufert, and M. Weidmann, “Reverse transcription recombinase polymerase amplification assay for the detection of Middle East respiratory syndrome coronavirus,” PLoS Currents, vol. 5, 2013. View at: Publisher Site | Google Scholar
  52. T. Yan, X. N. Li, L. Wang et al., “Development of a reverse transcription recombinase-aided amplification assay for the detection of coxsackievirus A10 and coxsackievirus A6 RNA,” Archives of Virology, vol. 163, no. 6, pp. 1455–1461, 2018. View at: Publisher Site | Google Scholar
  53. L. Cong, F. A. Ran, D. Cox et al., “Multiplex genome engineering using CRISPR/Cas systems,” Science, vol. 339, no. 6121, pp. 819–823, 2013. View at: Publisher Site | Google Scholar
  54. P. D. Hsu, E. S. Lander, and F. Zhang, “Development and applications of CRISPR-Cas9 for genome engineering,” Cell, vol. 157, no. 6, pp. 1262–1278, 2014. View at: Publisher Site | Google Scholar
  55. D. Cyranoski, “CRISPR gene-editing tested in a person for the first time,” Nature, vol. 539, no. 7630, p. 479, 2016. View at: Publisher Site | Google Scholar
  56. H. Rezaei, S. khadempar, N. Farahani et al., “Harnessing CRISPR/Cas9 technology in cardiovascular disease,” Trends in Cardiovascular Medicine, vol. 30, no. 2, pp. 93–101, 2020. View at: Publisher Site | Google Scholar
  57. J. S. Gootenberg, O. O. Abudayyeh, J. W. Lee et al., “Nucleic acid detection with CRISPR-Cas13a/C2c2,” Science, vol. 356, no. 6336, pp. 438–442, 2017. View at: Publisher Site | Google Scholar
  58. M. J. Kellner, J. G. Koob, J. S. Gootenberg, O. O. Abudayyeh, and F. Zhang, “SHERLOCK: nucleic acid detection with CRISPR nucleases,” Nature Protocols, vol. 14, no. 10, pp. 2986–3012, 2019. View at: Publisher Site | Google Scholar
  59. J. S. Gootenberg, O. O. Abudayyeh, M. J. Kellner, J. Joung, J. J. Collins, and F. Zhang, “Multiplexed and portable nucleic acid detection platform with Cas13, Cas12a, and Csm6,” Science, vol. 360, no. 6387, pp. 439–444, 2018. View at: Publisher Site | Google Scholar
  60. F. Zhang, O. O. Abudayyeh, and S. G. Jonathan, SHERLOCK, a protocol for detection of COVID-19 using CRISPR diagnostics, 2020,
  61. J. S. Chen, E. Ma, L. B. Harrington et al., “CRISPR-Cas12a target binding unleashes indiscriminate single-stranded DNase activity,” Science, vol. 360, no. 6387, pp. 436–439, 2018. View at: Publisher Site | Google Scholar
  62. C. Lucia, P.-B. Federico, and G. C. Alejandra, An ultrasensitive, rapid, and portable coronavirus SARS-CoV-2 sequence detection method based on CRISPR-Cas12, BioRxiv, 2020. View at: Publisher Site
  63. J. P. Broughton, X. Deng, G. Yu et al., “CRISPR-Cas12-based detection of SARS-CoV-2,” Nature Biotechnology, pp. 1–5, 2020. View at: Publisher Site | Google Scholar
  64. B. Vogelstein and K. W. Kinzler, “Digital PCR,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 16, pp. 9236–9241, 1999. View at: Publisher Site | Google Scholar
  65. D. Kim, Q. Wei, J. E. Kong, A. Ozcan, and D. Di Carlo, “Research highlights: digital assays on chip,” Lab on a Chip, vol. 15, no. 1, pp. 17–22, 2015. View at: Publisher Site | Google Scholar
  66. P. S. Dittrich and A. Manz, “Lab-on-a-chip: microfluidics in drug discovery,” Nature Reviews Drug Discovery, vol. 5, no. 3, pp. 210–218, 2006. View at: Publisher Site | Google Scholar
  67. G. M. Whitesides, “The origins and the future of microfluidics,” Nature, vol. 442, no. 7101, pp. 368–373, 2006. View at: Publisher Site | Google Scholar
  68. E. K. Sackmann, A. L. Fulton, and D. J. Beebe, “The present and future role of microfluidics in biomedical research,” Nature, vol. 507, no. 7491, pp. 181–189, 2014. View at: Publisher Site | Google Scholar
  69. J. E. Kreutz, T. Munson, T. Huynh, F. Shen, W. du, and R. F. Ismagilov, “Theoretical design and analysis of multivolume digital assays with wide dynamic range validated experimentally with microfluidic digital PCR,” Analytical Chemistry, vol. 83, no. 21, pp. 8158–8168, 2011. View at: Publisher Site | Google Scholar
  70. Y. Xia, S. Yan, X. Zhang et al., “Monte Carlo modeling-based digital loop-mediated isothermal amplification on a spiral chip for absolute quantification of nucleic acids,” Analytical Chemistry, vol. 89, no. 6, pp. 3716–3723, 2017. View at: Publisher Site | Google Scholar
  71. E. A. Ottesen, J. W. Hong, S. R. Quake, and J. R. Leadbetter, “Microfluidic digital PCR enables multigene analysis of individual environmental bacteria,” Science, vol. 314, no. 5804, pp. 1464–1467, 2006. View at: Publisher Site | Google Scholar
  72. A. Gansen, A. M. Herrick, I. K. Dimov, L. P. Lee, and D. T. Chiu, “Digital LAMP in a sample self-digitization (SD) chip,” Lab on a Chip, vol. 12, no. 12, pp. 2247–2254, 2012. View at: Publisher Site | Google Scholar
  73. Q. Zhu, Y. Gao, B. Yu et al., “Self-priming compartmentalization digital LAMP for point-of-care,” Lab on a Chip, vol. 12, no. 22, pp. 4755–4763, 2012. View at: Publisher Site | Google Scholar
  74. T. D. Rane, L. Chen, H. C. Zec, and T.-H. Wang, “Microfluidic continuous flow digital loop-mediated isothermal amplification (LAMP),” Lab on a Chip, vol. 15, no. 3, pp. 776–782, 2015. View at: Publisher Site | Google Scholar
  75. N. R. Y. Ho, G. S. Lim, N. R. Sundah, D. Lim, T. P. Loh, and H. Shao, “Visual and modular detection of pathogen nucleic acids with enzyme-DNA molecular complexes,” Nature Communications, vol. 9, no. 1, pp. 3211–3238, 2018. View at: Publisher Site | Google Scholar
  76. NUSnews, NUS scientists work on COVID-19 vaccine trial and rapid test kits, 2020,
  77. S. K. P. Lau, P. C. Y. Woo, B. H. L. Wong et al., “Detection of severe acute respiratory syndrome (SARS) coronavirus nucleocapsid protein in sars patients by enzyme-linked immunosorbent assay,” Journal of Clinical Microbiology, vol. 42, no. 7, pp. 2884–2889, 2004. View at: Publisher Site | Google Scholar
  78. Rockland Immunochemicals, I. ELISA Assays, 2020,
  79. P. C. Y. Woo, S. K. P. Lau, B. H. L. Wong et al., “Differential sensitivities of severe acute respiratory syndrome (SARS) coronavirus spike polypeptide enzyme-linked immunosorbent assay (ELISA) and SARS coronavirus nucleocapsid protein ELISA for serodiagnosis of SARS coronavirus pneumonia,” Journal of Clinical Microbiology, vol. 43, no. 7, pp. 3054–3058, 2005. View at: Publisher Site | Google Scholar
  80. N. Dennis, Singapore claims first use of antibody test to track coronavirus infections, 2020,
  81. C. Wang, W. Li, D. Drabek et al., A human monoclonal antibody blocking SARS-CoV-2 infection, BioRxiv, 2020. View at: Publisher Site
  82. W. Zhang, R. H. du, B. Li et al., “Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes,” Emerging Microbes & Infections, vol. 9, no. 1, pp. 386–389, 2020. View at: Publisher Site | Google Scholar
  83. R. Racine and G. M. Winslow, “IgM in microbial infections: taken for granted?” Immunology Letters, vol. 125, no. 2, pp. 79–85, 2009. View at: Publisher Site | Google Scholar
  84. Z. Li, Y. Yi, X. Luo et al., “Development and clinical application of a rapid IgM-IgG combined antibody test for SARS-CoV-2 infection diagnosis,” Journal of Medical Virology, 2020. View at: Publisher Site | Google Scholar
  85. M. Hosseiny, S. Kooraki, A. Gholamrezanezhad, S. Reddy, and L. Myers, “Radiology perspective of coronavirus disease 2019 (COVID-19): lessons from severe acute respiratory syndrome and Middle East respiratory syndrome,” AJR American Journal of Roentgenology, vol. 214, no. 5, pp. 1078–1082, 2020. View at: Publisher Site | Google Scholar
  86. L. Ketai, N. S. Paul, and K. T. Wong, “Radiology of severe acute respiratory syndrome (SARS): the emerging pathologic-radiologic correlates of an emerging disease,” Journal of Thoracic Imaging, vol. 21, no. 4, pp. 276–283, 2006. View at: Publisher Site | Google Scholar
  87. K. M. Das, E. Y. Lee, R. D. Langer, and S. G. Larsson, “Middle East respiratory syndrome coronavirus: what does a radiologist need to know?” American Journal of Roentgenology, vol. 206, no. 6, pp. 1193–1201, 2016. View at: Publisher Site | Google Scholar
  88. K. M. Das, E. Y. Lee, R. Singh et al., “Follow-up chest radiographic findings in patients with MERS-CoV after recovery,” Indian Journal of Radiology and Imaging, vol. 27, no. 3, pp. 342–349, 2017. View at: Publisher Site | Google Scholar
  89. G. E. Antonio, K. T. Wong, E. L. H. Tsui et al., “Chest radiograph scores as potential prognostic indicators in severe acute respiratory syndrome (SARS),” American Journal of Roentgenology, vol. 184, no. 3, pp. 734–741, 2005. View at: Publisher Site | Google Scholar
  90. M. Chung, A. Bernheim, X. Mei et al., “CT imaging features of 2019 novel coronavirus (2019-nCoV),” Radiology, vol. 295, no. 1, pp. 202–207, 2020. View at: Publisher Site | Google Scholar
  91. J. F.-W. Chan, S. Yuan, K. H. Kok et al., “A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster,” The Lancet, vol. 395, no. 10223, pp. 514–523, 2020. View at: Publisher Site | Google Scholar
  92. P. Liu and X. Z. Tan, “2019 novel coronavirus (2019-nCoV) pneumonia,” Radiology, vol. 295, no. 1, p. 19, 2020. View at: Publisher Site | Google Scholar
  93. The Guardian, What happens to people's lungs when they get coronavirus? 2020,
  94. A. Curry, H. Appleton, and B. Dowsett, “Application of transmission electron microscopy to the clinical study of viral and bacterial infections: present and future,” Micron, vol. 37, no. 2, pp. 91–106, 2006. View at: Publisher Site | Google Scholar
  95. X. Liu, R. Deng, Y. Zhang et al., “Probing the nature of upconversion nanocrystals: instrumentation matters,” Chemical Society Reviews, vol. 44, no. 6, pp. 1479–1508, 2015. View at: Publisher Site | Google Scholar
  96. R. Fernandez-Leiro and S. H. W. Scheres, “Unravelling biological macromolecules with cryo-electron microscopy,” Nature, vol. 537, no. 7620, pp. 339–346, 2016. View at: Publisher Site | Google Scholar
  97. Bloomberg, Here are the first images of how coronavirus replicates in cells, 2020,
  98. M. K. Monninger, C. A. Nguessan, C. D. Blancett et al., “Preparation of viral samples within biocontainment for ultrastructural analysis: utilization of an innovative processing capsule for negative staining,” Journal of Virological Methods, vol. 238, pp. 70–76, 2016. View at: Publisher Site | Google Scholar
  99. R. Xiong, L. Zhang, S. Li et al., Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2, BioRxiv, 2020. View at: Publisher Site
  100. J. W. Astin, P. Keerthisinghe, L. Du, L. E. Sanderson, K. E. Crosier, and C. J. Hall, “Innate immune cells and bacterial infection in zebrafish,” in Methods in Cell Biology, H. W. Detrich, M. Westerfield, and L. I. Zon, Eds., vol. 138, pp. 31–60, Academic Press, 2017. View at: Google Scholar
  101. T. I. Oprea, J. E. Bauman, C. G. Bologa et al., “Drug repurposing from an academic perspective,” Drug Discovery Today: Therapeutic Strategies, vol. 8, no. 3-4, pp. 61–69, 2011. View at: Publisher Site | Google Scholar
  102. A. Pizzorno, B. Padey, O. Terrier, and M. Rosa-Calatrava, “Drug repurposing approaches for the treatment of influenza viral infection: reviving old drugs to fight against a long-lived enemy,” Frontiers in Immunology, vol. 10, p. 531, 2019. View at: Publisher Site | Google Scholar
  103. R. Vardanyan and V. Hruby, “Chapter 34 - Antiviral Drugs,” in Synthesis of Best-Seller Drugs, R. Vardanyan and V. Hruby, Eds., pp. 687–736, Academic Press, 2016. View at: Publisher Site | Google Scholar
  104. W. Tai, L. He, X. Zhang et al., “Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine,” Cellular & Molecular Immunology, 2020. View at: Publisher Site | Google Scholar
  105. N. Wang, J. Shang, S. Jiang, and L. Du, “Subunit vaccines against emerging pathogenic human coronaviruses,” Frontiers in Microbiology, vol. 11, 2020. View at: Publisher Site | Google Scholar
  106. L. Du, W. Tai, Y. Zhou, and S. Jiang, “Vaccines for the prevention against the threat of MERS-CoV,” Expert Review of Vaccines, vol. 15, no. 9, pp. 1123–1134, 2016. View at: Publisher Site | Google Scholar
  107. Y. Zhou, S. Jiang, and L. Du, “Prospects for a MERS-CoV spike vaccine,” Expert Review of Vaccines, vol. 17, no. 8, pp. 677–686, 2018. View at: Publisher Site | Google Scholar
  108. S. Belouzard, J. K. Millet, B. N. Licitra, and G. R. Whittaker, “Mechanisms of coronavirus cell entry mediated by the viral spike protein,” Viruses, vol. 4, no. 6, pp. 1011–1033, 2012. View at: Publisher Site | Google Scholar
  109. W. Li, M. J. Moore, N. Vasilieva et al., “Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus,” Nature, vol. 426, no. 6965, pp. 450–454, 2003. View at: Publisher Site | Google Scholar
  110. V. S. Raj, H. Mou, S. L. Smits et al., “Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC,” Nature, vol. 495, no. 7440, pp. 251–254, 2013. View at: Publisher Site | Google Scholar
  111. Y. Chen, Y. Guo, Y. Pan, and Z. J. Zhao, “Structure analysis of the receptor binding of 2019-nCoV,” Biochemical and Biophysical Research Communications, vol. 525, no. 1, pp. 135–140, 2020. View at: Publisher Site | Google Scholar
  112. M. Letko, A. Marzi, and V. Munster, “Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses,” Nature Microbiology, vol. 5, no. 4, pp. 562–569, 2020. View at: Publisher Site | Google Scholar
  113. M. Hoffmann, H. Kleine-Weber, S. Schroeder et al., “SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor,” Cell, vol. 181, no. 2, pp. 271–280.e8, 2020. View at: Publisher Site | Google Scholar
  114. M. J. Huentelman, J. Zubcevic, J. A. Hernández Prada et al., “Structure-based discovery of a novel angiotensin-converting enzyme 2 inhibitor,” Hypertension, vol. 44, no. 6, pp. 903–906, 2004. View at: Publisher Site | Google Scholar
  115. T. Qaradakhi, L. K. Gadanec, K. R. McSweeney et al., “The potential actions of angiotensin converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases,” Clinical and Experimental Pharmacology and Physiology, vol. 47, no. 5, pp. 751–758, 2020. View at: Publisher Site | Google Scholar
  116. M. A. R. Chamsi-Pasha, Z. Shao, and W. H. W. Tang, “Angiotensin-converting enzyme 2 as a therapeutic target for heart failure,” Current Heart Failure Reports, vol. 11, no. 1, pp. 58–63, 2014. View at: Publisher Site | Google Scholar
  117. L. P. Hasvold, J. Bodegård, M. Thuresson et al., “Diabetes and CVD risk during angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment in hypertension: a study of 15 990 patients,” Journal of human hypertension, vol. 28, no. 11, pp. 663–669, 2014. View at: Publisher Site | Google Scholar
  118. W. B. White, C. Wilson, G. Bakris et al., “Ace inhibitor use and major cardiovascular outcomes in type 2 diabetes treated with the dpp-4 inhibitor alogliptin,” Journal of the American College of Cardiology, vol. 65, no. 10, article A1411, 2015. View at: Publisher Site | Google Scholar
  119. G. I. Rice, D. A. Thomas, P. J. Grant, A. J. Turner, and N. M. Hooper, “Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism,” Biochemical Journal, vol. 383, no. 1, pp. 45–51, 2004. View at: Publisher Site | Google Scholar
  120. A. B. Patel and A. Verma, “COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor Blockers,” The Journal of the American Medical Association, vol. 323, no. 18, pp. 1749–1862, 2020. View at: Publisher Site | Google Scholar
  121. L. Fang, G. Karakiulakis, and M. Roth, “Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?” The Lancet Respiratory Medicine, vol. 8, no. 4, article e21, 2020. View at: Publisher Site | Google Scholar
  122. R. U. Kadam and I. A. Wilson, “Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol,” Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 2, pp. 206–214, 2017. View at: Publisher Site | Google Scholar
  123. Z. Shen, K. Lou, and W. Wang, “New small-molecule drug design strategies for fighting resistant influenza A,” Acta Pharmaceutica Sinica B, vol. 5, no. 5, pp. 419–430, 2015. View at: Publisher Site | Google Scholar
  124. I. A. Leneva, R. J. Russell, Y. S. Boriskin, and A. J. Hay, “Characteristics of arbidol-resistant mutants of influenza virus: implications for the mechanism of anti-influenza action of arbidol,” Antiviral Research, vol. 81, no. 2, pp. 132–140, 2009. View at: Publisher Site | Google Scholar
  125. E. Teissier, G. Zandomeneghi, A. Loquet et al., “Mechanism of inhibition of enveloped virus membrane fusion by the antiviral drug arbidol,” PLoS One, vol. 6, no. 1, article e15874, 2011. View at: Publisher Site | Google Scholar
  126. J. Villalaín, “Membranotropic effects of arbidol, a broad anti-viral molecule, on phospholipid model membranes,” The Journal of Physical Chemistry B, vol. 114, no. 25, pp. 8544–8554, 2010. View at: Publisher Site | Google Scholar
  127. Z. Wang, X. Chen, Y. Lu, F. Chen, and W. Zhang, “Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment,” BioScience Trends, vol. 14, no. 1, pp. 64–68, 2020. View at: Publisher Site | Google Scholar
  128. L. Dong, S. Hu, and J. Gao, “Discovering drugs to treat coronavirus disease 2019 (COVID-19),” Drug Discoveries & Therapeutics, vol. 14, no. 1, pp. 58–60, 2020. View at: Publisher Site | Google Scholar
  129. A. Savarino, J. R. Boelaert, A. Cassone, G. Majori, and R. Cauda, “Effects of chloroquine on viral infections: an old drug against today's diseases,” The Lancet Infectious Diseases, vol. 3, no. 11, pp. 722–727, 2003. View at: Publisher Site | Google Scholar
  130. B. Poole and S. Ohkuma, “Effect of weak bases on the intralysosomal pH in mouse peritoneal macrophages,” Journal of Cell Biology, vol. 90, no. 3, pp. 665–669, 1981. View at: Publisher Site | Google Scholar
  131. E. Schrezenmeier and T. Dörner, “Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology,” Nature Reviews Rheumatology, vol. 16, no. 3, pp. 155–166, 2020. View at: Publisher Site | Google Scholar
  132. M. Mauthe, I. Orhon, C. Rocchi et al., “Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion,” Autophagy, vol. 14, no. 8, pp. 1435–1455, 2018. View at: Publisher Site | Google Scholar
  133. A. Savarino, L. Di Trani, I. Donatelli, R. Cauda, and A. Cassone, “New insights into the antiviral effects of chloroquine,” The Lancet Infectious Diseases, vol. 6, no. 2, pp. 67–69, 2006. View at: Publisher Site | Google Scholar
  134. A. Savarino, M. B. Lucia, E. Rastrelli et al., “Anti-HIV effects of chloroquine: inhibition of viral particle glycosylation and synergism with protease inhibitors,” JAIDS Journal of Acquired Immune Deficiency Syndromes, vol. 35, no. 3, pp. 223–232, 2004. View at: Publisher Site | Google Scholar
  135. J. Liu, R. Cao, M. Xu et al., “Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro,” Cell Discovery, vol. 6, no. 1, p. 16, 2020. View at: Publisher Site | Google Scholar
  136. M. J. Vincent, E. Bergeron, S. Benjannet et al., “Chloroquine is a potent inhibitor of SARS coronavirus infection and spread,” Virology Journal, vol. 2, no. 1, p. 69, 2005. View at: Publisher Site | Google Scholar
  137. E. Keyaerts, L. Vijgen, P. Maes, J. Neyts, and M. V. Ranst, “In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine,” Biochemical and Biophysical Research Communications, vol. 323, no. 1, pp. 264–268, 2004. View at: Publisher Site | Google Scholar
  138. M. Wang, R. Cao, L. Zhang et al., “Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro,” Cell Research, vol. 30, no. 3, pp. 269–271, 2020. View at: Publisher Site | Google Scholar
  139. J. Gao, Z. Tian, and X. Yang, “Breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies,” BioScience Trends, vol. 14, no. 1, pp. 72-73, 2020. View at: Publisher Site | Google Scholar
  140. P. Colson, J.-M. Rolain, J.-C. Lagier, P. Brouqui, and D. Raoult, “Chloroquine and hydroxychloroquine as available weapons to fight COVID-19,” International Journal of Antimicrobial Agents, vol. 55, no. 4, article 105932, 2020. View at: Publisher Site | Google Scholar
  141. X. Yao, F. Ye, M. Zhang et al., “In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),” Clinical Infectious Diseases, 2020. View at: Publisher Site | Google Scholar
  142. S. Pasadhika and G. A. Fishman, “Effects of chronic exposure to hydroxychloroquine or chloroquine on inner retinal structures,” Eye, vol. 24, no. 2, pp. 340–346, 2010. View at: Publisher Site | Google Scholar
  143. E. W. McChesney, “Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate,” The American Journal of Medicine, vol. 75, no. 1, pp. 11–18, 1983. View at: Publisher Site | Google Scholar
  144. J. Konvalinka, H.-G. Kräusslich, and B. Müller, “Retroviral proteases and their roles in virion maturation,” Virology, vol. 479-480, pp. 403–417, 2015. View at: Publisher Site | Google Scholar
  145. J. K. Millet and G. R. Whittaker, “Host cell proteases: critical determinants of coronavirus tropism and pathogenesis,” Virus Research, vol. 202, pp. 120–134, 2015. View at: Publisher Site | Google Scholar
  146. S. Bertram, A. Heurich, H. Lavender et al., “Influenza and SARS-coronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts,” PLoS One, vol. 7, no. 4, article e35876, 2012. View at: Publisher Site | Google Scholar
  147. C. Liu, Q. Zhou, Y. Li et al., “Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases,” ACS Central Science, vol. 6, no. 3, pp. 315–331, 2020. View at: Publisher Site | Google Scholar
  148. J. Ziebuhr, E. J. Snijder, and A. E. Gorbalenya, “Virus-encoded proteinases and proteolytic processing in the Nidovirales,” Journal of General Virology, vol. 81, no. 4, pp. 853–879, 2000. View at: Publisher Site | Google Scholar
  149. Y. M. Báez-Santos, S. E. St John, and A. D. Mesecar, “The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds,” Antiviral Research, vol. 115, pp. 21–38, 2015. View at: Publisher Site | Google Scholar
  150. T.-W. Lee, M. M. Cherney, C. Huitema et al., “Crystal Structures of the Main Peptidase from the SARS Coronavirus Inhibited by a Substrate-like Aza-peptide Epoxide,” Journal of Molecular Biology, vol. 353, no. 5, pp. 1137–1151, 2005. View at: Publisher Site | Google Scholar
  151. M. Kawase, K. Shirato, L. van der Hoek, F. Taguchi, and S. Matsuyama, “Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry,” Journal of Virology, vol. 86, no. 12, pp. 6537–6545, 2012. View at: Publisher Site | Google Scholar
  152. Y. Zhou, P. Vedantham, K. Lu et al., “Protease inhibitors targeting coronavirus and filovirus entry,” Antiviral Research, vol. 116, pp. 76–84, 2015. View at: Publisher Site | Google Scholar
  153. N. Ashizawa, T. Hashimoto, T. Miyake, T. Shizuku, T. Imaoka, and Y. Kinoshita, “Efficacy of camostat mesilate compared with famotidine for treatment of functional dyspepsia: is camostat mesilate effective?” Journal of Gastroenterology and Hepatology, vol. 21, no. 4, pp. 767–771, 2006. View at: Publisher Site | Google Scholar
  154. J. Gibo, T. Ito, K. Kawabe et al., “Camostat mesilate attenuates pancreatic fibrosis via inhibition of monocytes and pancreatic stellate cells activity,” Laboratory Investigation, vol. 85, no. 1, pp. 75–89, 2005. View at: Publisher Site | Google Scholar
  155. H. Ishikura, S. Nishimura, M. Matsunami et al., “The proteinase inhibitor camostat mesilate suppresses pancreatic pain in rodents,” Life Sciences, vol. 80, no. 21, pp. 1999–2004, 2007. View at: Publisher Site | Google Scholar
  156. K. Shirato, M. Kawase, and S. Matsuyama, “Middle East respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2,” Journal of Virology, vol. 87, no. 23, pp. 12552–12561, 2013. View at: Publisher Site | Google Scholar
  157. E. De Clercq, “Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV,” International Journal of Antimicrobial Agents, vol. 33, no. 4, pp. 307–320, 2009. View at: Publisher Site | Google Scholar
  158. M. W. Hull and J. S. G. Montaner, “Ritonavir-boosted protease inhibitors in HIV therapy,” Annals of Medicine, vol. 43, no. 5, pp. 375–388, 2011. View at: Publisher Site | Google Scholar
  159. C. M. Chu, V. C. Cheng, I. F. Hung et al., “Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings,” Thorax, vol. 59, no. 3, pp. 252–256, 2004. View at: Publisher Site | Google Scholar
  160. X. Liu and X.-J. Wang, “Potential inhibitors against 2019-nCoV coronavirus M protease from clinically approved medicines,” Journal of Genetics and Genomics, vol. 47, no. 2, pp. 119–121, 2020. View at: Publisher Site | Google Scholar
  161. B. Cao, Y. Wang, D. Wen et al., “A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19,” The New England Journal of Medicine, vol. 382, pp. 1787–1799, 2020. View at: Publisher Site | Google Scholar
  162. J. Chen, Z. Liang, W. Wang, C. Yi, S. Zhang, and Q. Zhang, “Revealing origin of decrease in potency of darunavir and amprenavir against HIV-2 relative to HIV-1 protease by molecular dynamics simulations,” Scientific Reports, vol. 4, article 6872, 2015. View at: Publisher Site | Google Scholar
  163. H. Hayashi, N. Takamune, T. Nirasawa et al., “Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 33, pp. 12234–12239, 2014. View at: Publisher Site | Google Scholar
  164. S. Lin, R. Shen, J. He, X. Li, and X. Guo, Molecular modeling evaluation of the binding effect of ritonavir, lopinavir and darunavir to severe acute respiratory syndrome coronavirus 2 proteases, bioRxiv, 2020. View at: Publisher Site
  165. B. J. Eckhardt and R. M. Gulick, “Drugs for HIV Infection,” in Infectious Diseases (Fourth Edition), J. Cohen, W. G. Powderly, and S. M. Opal, Eds., pp. 1293–1308. e2, Elsevier, 2017. View at: Publisher Site | Google Scholar
  166. J. Magden, L. Kääriäinen, and T. Ahola, “Inhibitors of virus replication: recent developments and prospects,” Applied Microbiology and Biotechnology, vol. 66, no. 6, pp. 612–621, 2005. View at: Publisher Site | Google Scholar
  167. J. Lung, Y. S. Lin, Y. H. Yang et al., “The potential chemical structure of anti-SARS-CoV-2 RNA-dependent RNA polymerase,” Journal of Medical Virology, vol. 92, no. 6, pp. 693–697, 2020. View at: Publisher Site | Google Scholar
  168. E. Thomas, M. G. Ghany, and T. J. Liang, “The application and mechanism of action of ribavirin in therapy of hepatitis C,” Antiviral Chemistry and Chemotherapy, vol. 23, no. 1, pp. 1–12, 2012. View at: Publisher Site | Google Scholar
  169. S. Crotty, D. Maag, J. J. Arnold et al., “The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen,” Nature Medicine, vol. 6, no. 12, pp. 1375–1379, 2000. View at: Publisher Site | Google Scholar
  170. D. Dulin, J. J. Arnold, T. van Laar et al., “Signatures of nucleotide analog incorporation by an RNA-dependent rna polymerase revealed using high-throughput magnetic tweezers,” Cell Reports, vol. 21, no. 4, pp. 1063–1076, 2017. View at: Publisher Site | Google Scholar
  171. G. Koren, S. King, S. Knowles, and E. Phillips, “Ribavirin in the treatment of SARS: a new trick for an old drug?” CMAJ, vol. 168, no. 10, pp. 1289–1292, 2003. View at: Google Scholar
  172. S. Crotty, C. E. Cameron, and R. Andino, “RNA virus error catastrophe: direct molecular test by using ribavirin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 12, pp. 6895–6900, 2001. View at: Publisher Site | Google Scholar
  173. H. S. Te, G. Randall, and D. M. Jensen, “Mechanism of action of ribavirin in the treatment of chronic hepatitis C,” Gastroenterology & Hepatology, vol. 3, no. 3, pp. 218–225, 2007. View at: Google Scholar
  174. D. Y. Tai, “Pharmacologic treatment of SARS: current knowledge and recommendations,” Annals Academy of Medicine, vol. 36, pp. 438–443, 2007. View at: Google Scholar
  175. J. Dyall, R. Gross, J. Kindrachuk et al., “Middle East respiratory syndrome and severe acute respiratory syndrome: current therapeutic options and potential targets for novel therapies,” Drugs, vol. 77, no. 18, pp. 1935–1966, 2017. View at: Publisher Site | Google Scholar
  176. J. A. Al-Tawfiq, H. Momattin, J. Dib, and Z. A. Memish, “Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study,” International Journal of Infectious Diseases, vol. 20, pp. 42–46, 2014. View at: Publisher Site | Google Scholar
  177. H. Momattin, K. Mohammed, A. Zumla, Z. A. Memish, and J. A. Al-Tawfiq, “Therapeutic Options for Middle East Respiratory Syndrome Coronavirus (MERS- CoV) – possible lessons from a systematic review of SARS-CoV therapy,” International Journal of Infectious Diseases, vol. 17, no. 10, pp. e792–e798, 2013. View at: Publisher Site | Google Scholar
  178. Y. P. Chong, J. Y. Song, Y. B. Seo, J. P. Choi, H. S. Shin, and Rapid Response Team, “Antiviral treatment guidelines for Middle East respiratory syndrome,” Infection & Chemotherapy, vol. 47, no. 3, pp. 212–222, 2015. View at: Publisher Site | Google Scholar
  179. R. Abdelnabi, A. T. S. . Morais, P. Leyssen et al., “Understanding the mechanism of the broad-spectrum antiviral activity of favipiravir (T-705): key role of the F1 motif of the viral polymerase,” Journal of Virology, vol. 91, no. 12, 2017. View at: Publisher Site | Google Scholar
  180. F. Pettini, A. Trezza, and O. Spiga, “A Focus on Ebola Virus Polymerase,” Viral Polymerases, pp. 181–210, 2019. View at: Publisher Site | Google Scholar
  181. Y. Furuta, B. B. Gowen, K. Takahashi, K. Shiraki, D. F. Smee, and D. L. Barnard, “Favipiravir (T-705), a novel viral RNA polymerase inhibitor,” Antiviral Research, vol. 100, no. 2, pp. 446–454, 2013. View at: Publisher Site | Google Scholar
  182. Y. Furuta, T. Komeno, and T. Nakamura, “Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase,” Proceedings of the Japan Academy, Series B, vol. 93, no. 7, pp. 449–463, 2017. View at: Publisher Site | Google Scholar
  183. Q. Cai, M. Yang, D. Liu et al., “Experimental treatment with favipiravir for COVID-19: an open-label control study,” Engineering, 2020. View at: Publisher Site | Google Scholar
  184. C. Chen et al., Favipiravir versus arbidol for COVID-19: a randomized clinical trial, medRxiv, 2020. View at: Publisher Site
  185. T. K. Warren, R. Jordan, M. K. Lo et al., “Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys,” Nature, vol. 531, no. 7594, pp. 381–385, 2016. View at: Publisher Site | Google Scholar
  186. J. A. Al-Tawfiq, A. H. Al-Homoud, and Z. A. Memish, “Remdesivir as a possible therapeutic option for the COVID-19,” Travel Medicine and Infectious Disease, vol. 34, 2020. View at: Publisher Site | Google Scholar
  187. T. P. Sheahan, A. C. Sims, S. R. Leist et al., “Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV,” Nature Communications, vol. 11, no. 1, p. 222, 2020. View at: Publisher Site | Google Scholar
  188. Centers for Disease Control and Prevention, Information for clinicians on therapeutic options for COVID-19 patients, 2020,
  189. Chinese Centre for Disease Control and Prevention, COVID-19 prevention and control: diagnosis and treatment, 2020,
  190. D. E. Anderson, J. Cui, Q. Ye et al., Orthogonal genome-wide screenings in bat cells identify MTHFD1 as a target of broad antiviral therapy, bioRxiv, 2020. View at: Publisher Site
  191. G. S. Ducker and J. D. Rabinowitz, “One-carbon metabolism in health and disease,” Cell Metabolism, vol. 25, no. 1, pp. 27–42, 2017. View at: Publisher Site | Google Scholar
  192. C. Apel, A. Barg, A. Rheinberg, G. Conrads, and I. Wagner-Döbler, “Dental composite materials containing carolacton inhibit biofilm growth of Streptococcus mutans,” Dental Materials, vol. 29, no. 11, pp. 1188–1199, 2013. View at: Publisher Site | Google Scholar
  193. J. Donner, M. Reck, B. Bunk et al., “The biofilm inhibitor carolacton enters gram-negative cells: studies using a TolC-deficient strain of Escherichia coli,” mSphere, vol. 2, no. 5, article e00375, 2017. View at: Publisher Site | Google Scholar
  194. B. Kunze, M. Reck, A. Dötsch et al., “Damage of Streptococcus mutans biofilms by carolacton, a secondary metabolite from the myxobacterium Sorangium cellulosum,” BMC Microbiology, vol. 10, no. 1, p. 199, 2010. View at: Publisher Site | Google Scholar
  195. S. Sainas, F. Dosio, D. Boschi, and M. L. Lolli, “Targeting human onchocerciasis: recent advances beyond ivermectin,” in Annual Reports in Medicinal Chemistry, M. Botta, Ed., vol. 51, pp. 1–8, Academic Press, Cambridge, MA, USA, 2018. View at: Google Scholar
  196. K. M. Wagstaff, H. Sivakumaran, S. M. Heaton, D. Harrich, and D. A. Jans, “Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus,” Biochemical Journal, vol. 443, no. 3, pp. 851–856, 2012. View at: Publisher Site | Google Scholar
  197. L. Caly, J. D. Druce, M. G. Catton, D. A. Jans, and K. M. Wagstaff, “The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro,” Antiviral Research, vol. 178, article 104787, 2020. View at: Publisher Site | Google Scholar
  198. R. Yang, J. Xu, L. Xu et al., “Cancer cell membrane-coated adjuvant nanoparticles with mannose modification for effective anticancer vaccination,” ACS Nano, vol. 12, no. 6, pp. 5121–5129, 2018. View at: Publisher Site | Google Scholar
  199. Q. Pei, X. Hu, X. Zheng et al., “Light-activatable red blood cell membrane-camouflaged dimeric prodrug nanoparticles for synergistic photodynamic/chemotherapy,” ACS Nano, vol. 12, no. 2, pp. 1630–1641, 2018. View at: Publisher Site | Google Scholar
  200. C. Yao, W. Wang, P. Wang, M. Zhao, X. Li, and F. Zhang, “Near-infrared upconversion mesoporous cerium oxide hollow biophotocatalyst for concurrent pH-/H2O2-responsive O2-evolving synergetic cancer therapy,” Advanced Materials, vol. 30, no. 7, article 1704833, 2018. View at: Publisher Site | Google Scholar
  201. G. Gao, Y.-W. Jiang, H.-R. Jia, and F.-G. Wu, “Near-infrared light-controllable on-demand antibiotics release using thermo- sensitive hydrogel-based drug reservoir for combating bacterial infection,” Biomaterials, vol. 188, pp. 83–95, 2019. View at: Publisher Site | Google Scholar
  202. J. Marcandalli, B. Fiala, S. Ols et al., “Induction of potent neutralizing antibody responses by a designed protein nanoparticle vaccine for respiratory syncytial virus,” Cell, vol. 176, no. 6, pp. 1420–1431.e17, 2019. View at: Publisher Site | Google Scholar
  203. M. Rai, S. D. Deshmukh, A. P. Ingle, I. R. Gupta, M. Galdiero, and S. Galdiero, “Metal nanoparticles: the protective nanoshield against virus infection,” Critical Reviews in Microbiology, vol. 42, no. 1, pp. 46–56, 2014. View at: Publisher Site | Google Scholar
  204. N. G. Portney and M. Ozkan, “Nano-oncology: drug delivery, imaging, and sensing,” Analytical and Bioanalytical Chemistry, vol. 384, no. 3, pp. 620–630, 2006. View at: Publisher Site | Google Scholar
  205. Y. Fujimori, T. Sato, T. Hayata et al., “Novel antiviral characteristics of nanosized copper(I) iodide particles showing inactivation activity against 2009 pandemic H1N1 influenza virus,” Applied and Environmental Microbiology, vol. 78, no. 4, pp. 951–955, 2012. View at: Publisher Site | Google Scholar
  206. S. Galdiero, A. Falanga, M. Vitiello, M. Cantisani, V. Marra, and M. Galdiero, “Silver nanoparticles as potential antiviral agents,” Molecules, vol. 16, no. 10, pp. 8894–8918, 2011. View at: Publisher Site | Google Scholar
  207. S. Herold and L.-E. Sander, “Toward a universal flu vaccine,” Science, vol. 367, no. 6480, pp. 852-853, 2020. View at: Publisher Site | Google Scholar
  208. K. Shen, Y. Yang, T. Wang et al., “Diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts’ consensus statement,” World Journal of Pediatrics, 2020. View at: Publisher Site | Google Scholar
  209. Z.-M. Chen, J. F. Fu, Q. Shu et al., “Diagnosis and treatment recommendations for pediatric respiratory infection caused by the 2019 novel coronavirus,” World Journal of Pediatrics, 2020. View at: Publisher Site | Google Scholar
  210. A. Casadevall and L. Pirofski, “The convalescent sera option for containing COVID-19,” Journal of Clinical Investigation, vol. 130, no. 4, pp. 1545–1548, 2020. View at: Publisher Site | Google Scholar
  211. L. Chen, J. Xiong, L. Bao, and Y. Shi, “Convalescent plasma as a potential therapy for COVID-19,” The Lancet Infectious Diseases, vol. 20, no. 4, pp. 398–400, 2020. View at: Publisher Site | Google Scholar
  212. A. Maxmen, “More than 80 clinical trials launch to test coronavirus treatments,” Nature, vol. 578, no. 7795, pp. 347-348, 2020. View at: Publisher Site | Google Scholar
  213. Pharmaceutical, T, Takeda initiates development of a plasma-derived therapy for COVID-19, 2020,
  214. X. Tian, C. Li, A. Huang et al., “Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody,” Emerging Microbes & Infections, vol. 9, no. 1, pp. 382–385, 2020. View at: Publisher Site | Google Scholar
  215. E. Villamor, R. Mbise, D. Spiegelman et al., “Vitamin A supplements ameliorate the adverse effect of HIV-1, malaria, and diarrheal infections on child growth,” Pediatrics, vol. 109, no. 1, article e6, 2002. View at: Publisher Site | Google Scholar
  216. P. P. Glasziou and D. E. Mackerras, “Vitamin A supplementation in infectious diseases: a meta-analysis,” BMJ, vol. 306, no. 6874, pp. 366–370, 1993. View at: Publisher Site | Google Scholar
  217. H. Hemilä, “Vitamin C and SARS coronavirus,” Journal of Antimicrobial Chemotherapy, vol. 52, no. 6, pp. 1049-1050, 2003. View at: Publisher Site | Google Scholar
  218. H. Hemilä, “Vitamin C intake and susceptibility to pneumonia,” The Pediatric Infectious Disease Journal, vol. 16, no. 9, pp. 836-837, 1997. View at: Publisher Site | Google Scholar
  219. A. R. Martineau, D. A. Jolliffe, R. L. Hooper et al., “Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data,” BMJ, vol. 356, article i6583, 2017. View at: Publisher Site | Google Scholar
  220. A. J. W. te Velthuis, S. H. E. van den Worm, A. C. Sims, R. S. Baric, E. J. Snijder, and M. J. van Hemert, “Zn2+ inhibits coronavirus and arterivirus rna polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture,” PLoS Pathogens, vol. 6, no. 11, article e1001176, 2010. View at: Publisher Site | Google Scholar
  221. Z. S. Lassi, A. Moin, Z. A. Bhutta, and Cochrane Acute Respiratory Infections Group, “Zinc supplementation for the prevention of pneumonia in children aged 2 months to 59 months,” Cochrane Database of Systematic Reviews, vol. 12, article CD005978, 2016. View at: Publisher Site | Google Scholar
  222. C. Alberda, L. Gramlich, N. Jones et al., “The relationship between nutritional intake and clinical outcomes in critically ill patients: results of an international multicenter observational study,” Intensive Care Medicine, vol. 35, no. 10, pp. 1728–1737, 2009. View at: Publisher Site | Google Scholar
  223. M. Kalaiselvan, M. K. Renuka, and A. S. Arunkumar, “Use of nutrition risk in critically ill (NUTRIC) score to assess nutritional risk in mechanically ventilated patients: a prospective observational study,” Indian Journal of Critical Care Medicine, vol. 21, no. 5, pp. 253–256, 2017. View at: Publisher Site | Google Scholar
  224. X. Yang, Y. Yu, J. Xu et al., “Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study,” The Lancet Respiratory Medicine, vol. 8, no. 5, pp. 475–481, 2020. View at: Publisher Site | Google Scholar
  225. Z. Wu and J. M. McGoogan, “Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China,” JAMA, vol. 323, no. 13, pp. 1239–1242, 2020. View at: Publisher Site | Google Scholar
  226. H.-Y. Kim, H. S. Shin, H. Park et al., “In vitro inhibition of coronavirus replications by the traditionally used medicinal herbal extracts, Cimicifuga rhizoma, Meliae cortex, Coptidis rhizoma, and Phellodendron cortex,” Journal of Clinical Virology, vol. 41, no. 2, pp. 122–128, 2008. View at: Publisher Site | Google Scholar
  227. J.-R. Weng, C. S. Lin, H. C. Lai et al., “Antiviral activity of Sambucus FormosanaNakai ethanol extract and related phenolic acid constituents against human coronavirus NL63,” Virus Research, vol. 273, article 197767, 2019. View at: Publisher Site | Google Scholar
  228. L.-x. Nie, Y.-l. Wu, Z. Dai, and S.-c. Ma, “Antiviral activity of Isatidis Radix derived glucosinolate isomers and their breakdown products against influenza A in vitro/ovo and mechanism of action,” Journal of Ethnopharmacology, vol. 251, 2020. View at: Publisher Site | Google Scholar
  229. J. Ren, A.-H. Zhang, and X.-J. Wang, “Traditional Chinese medicine for COVID-19 treatment,” Pharmacological Research, vol. 155, article 104743, 2020. View at: Publisher Site | Google Scholar
  230. Y. Han, M. R. Zhao, B. Shi, Z. H. Song, S. P. Zhou, and Y. He, “Application of integrative medicine protocols on treatment of coronavirus disease 2019,” Chinese Traditional and Herbal Drugs, vol. 51, pp. 878–882, 2020. View at: Google Scholar
  231. Publicity Department of the People's Republic of China, Press conference of the joint prevention and control mechanism of state council on Feb 17, 2020.,
  232. Y. Song, C. Yao, Y. Yao et al., “XueBiJing injection versus placebo for critically ill patients with severe community-acquired pneumonia: a randomized controlled trial,” Critical Care Medicine, vol. 47, no. 9, pp. e735–e743, 2019. View at: Publisher Site | Google Scholar
  233. P. Van Pham and N. K. Phan, “Welcome to progress in stem cell,” Progress in Stem Cell, vol. 1, no. 1, pp. 1-2, 2014. View at: Publisher Site | Google Scholar
  234. J. Chen, C. Hu, L. Chen et al., “Clinical study of mesenchymal stem cell treatment for acute respiratory distress syndrome induced by epidemic influenza A (H7N9) infection: a hint for COVID-19 treatment,” Engineering, 2020. View at: Publisher Site | Google Scholar
  235. B. Liang, J. Chen, T. Li et al., Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells, ChinaXiv, 2020.
  236. Z. Leng, R. Zhu, W. Hou et al., “Transplantation of ACE2-mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia,” Aging and Disease, vol. 11, no. 2, pp. 216–228, 2020. View at: Publisher Site | Google Scholar
  237. National Institutes of Health (NIH), NIH clinical trial of investigational vaccine for COVID-19 begins, 2020,
  238. Bioworld, China approves first homegrown COVID-19 vaccine to enter clinical trials, 2020,
  239. DRAFT landscape of COVID-19 candidate vaccines-20 March, 2020, 2020,
  240. M. H. Wolff, S. A. Sattar, O. Adegbunrin, and J. Tetro, “Environmental survival and microbicide inactivation of coronaviruses,” in Coronaviruses with Special Emphasis on First Insights Concerning SARS, A. Schmidt, O. Weber, and M. H. Wolff, Eds., pp. 201–212, Birkhäuser Advances in Infectious Diseases BAID, Birkhäuser Basel, 2005. View at: Publisher Site | Google Scholar
  241. N. van Doremalen, T. Bushmaker, D. H. Morris et al., “Aerosol and surface stability of SARS-CoV-2 as compared with SARS-CoV-1,” New England Journal of Medicine, vol. 382, no. 16, pp. 1564–1567, 2020. View at: Publisher Site | Google Scholar
  242. S. Salehi, A. Abedi, S. Balakrishnan, and A. Gholamrezanezhad, “Coronavirus disease 2019 (COVID-19): a systematic review of imaging findings in 919 patients,” American Journal of Roentgenology, pp. 1–7, 2020. View at: Publisher Site | Google Scholar
  243. Key export products for COVID-19 diagnosis & treatment, 2020,
  244. University of Nankai develops rapid test kit, 2020,
  245. Researchers develop new test kit to detect coronavirus in 15 mins, 2020,
  246. China approves 29-minute testing kit for new coronavirus, 2020,
  247. S'pore researchers invent Covid-19 test that can tell if someone's infected in 5 minutes, 2020,
  248. J. P. Broughton, W. Deng, C. L. Fasching, J. Singh, C. Y. Chiu, and J. S. Chen, A protocol for rapid detection of the 2019 novel coronavirus SARS-CoV-2 using CRISPR diagnostics: SARS-CoV-2 DETECTR, 2020,
  249. Channelnewsasia, New COVID-19 test kits used to screen swab samples collected at Singapore checkpoints, 2020,
  250. Beihang University, The development of Beihang University on detecting and preventing of 2019-nCoV, 2020,
  251. S. F. Ahmed, A. A. Quadeer, and M. R. McKay, “Preliminary identification of potential vaccine targets for the COVID-19 coronavirus (SARS-CoV-2) based on SARS-CoV immunological studies,” Viruses, vol. 12, no. 3, p. 254, 2020. View at: Publisher Site | Google Scholar
  252. Q. Li, J. Yin, Q. S. Ran et al., “Efficacy and mechanism of Lianhua Qingwen Capsules(LHQW) on chemotaxis of macrophages in acute lung injury (ALI) animal model,” China Journal of Chinese Materia Medica, vol. 44, no. 11, pp. 2317–2323, 2019. View at: Publisher Site | Google Scholar
  253. X. Chen, Y. Feng, X. Shen et al., “Anti-sepsis protection of Xuebijing injection is mediated by differential regulation of pro- and anti-inflammatory Th17 and T regulatory cells in a murine model of polymicrobial sepsis,” Journal of Ethnopharmacology, vol. 211, pp. 358–365, 2018. View at: Publisher Site | Google Scholar
  254. Y. Zhang, B. Chi-Yan Cheng, R. Xie, B. Xu, X. Y. Gao, and G. Luo, “Re-Du-Ninginhalation solution exerts suppressive effect on the secretion of inflammatory mediatorsviainhibiting IKKα/β/IκBα/NF-κB, MAPKs/AP-1, and TBK1/IRF3 signaling pathways in lipopolysaccharide stimulated RAW 264.7 macrophages,” RSC Advances, vol. 9, no. 16, pp. 8912–8925, 2019. View at: Publisher Site | Google Scholar
  255. S. Peng, N. Hang, W. Liu et al., “Andrographolide sulfonate ameliorates lipopolysaccharide-induced acute lung injury in mice by down-regulating MAPK and NF-κB pathways,” Acta Pharmaceutica Sinica B, vol. 6, no. 3, pp. 205–211, 2016. View at: Publisher Site | Google Scholar
  256. W. Liu, H. L. Jiang, L. L. Cai, M. Yan, S. J. Dong, and B. Mao, “Tanreqing injection attenuates lipopolysaccharide-induced airway inflammation through MAPK/NF-κB signaling pathways in rats model,” Evidence-Based Complementary and Alternative Medicine, vol. 2016, Article ID 5292346, 15 pages, 2016. View at: Publisher Site | Google Scholar
  257. Y. Lyu, L. S. Fu, J. Zhou, J. Cai, X. Y. Chen, and H. L. Zhong, “Action mechanism of Shenfu injection by computational system biology analysis,” Chinese Journal of Experimental Traditional Medical Formulae, vol. 21, pp. 217–221, 2015. View at: Google Scholar

Copyright © 2020 Zichao Luo et al. Exclusive Licensee Science and Technology Review Publishing House. Distributed under a Creative Commons Attribution License (CC BY 4.0).

 PDF Download Citation Citation
Altmetric Score