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Research Update: A review of therapeutic agents and Chinese herbal medicines against SARS- COV-2 (COVID-19)

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Pharmacol Res. 2020 Aug; 158: 104929.

Published online 2020 May 20.  doi: 10.1016/j.phrs.2020.104929

PMCID: PMC7237953

PMID: 32442720

Fangfang Huang,a Ying Li,b Elaine Lai-Han Leung,c Xiaohua Liu,a Kaifeng Liu,d Qu Wang,d Yongqi Lan,d Xiaoling Li,e Haibing Yu,f Liao Cui,g Hui Luo,h and Lianxiang Luoh*

Abstract

The epidemic of pneumonia (COVID-19) caused by novel coronavirus (SARS-CoV-2) infection has been listed as a public health emergency of international concern by the World Health Organization (WHO), and its harm degree is defined as a global “pandemic”. At present, the efforts of various countries focus on the rapid diagnosis and isolation of patients, as well as to find a treatment that can combat the most serious impact of the disease. The number of reported COVID-19 virus infections is still increasing. Unfortunately, no drugs or vaccines have been approved for the treatment of human coronaviruses, but there is an urgent need for in-depth research on emerging human infectious coronaviruses. Clarification transmission routes and pathogenic mechanisms, and identification of potential drug treatment targets will promote the development of effective prevention and treatment measures. In the absence of confirmed effective treatments, due to public health emergencies, it is essential to study the possible effects of existing approved antivirals drugs or Chinese herbal medicines for SARS-CoV-2. This review summarizes the epidemiological characteristics, pathogenesis, virus structure and targeting strategies of COVID-19. Meanwhile, this review also focus on the re-purposing of clinically approved drugs and Chinese herbal medicines that may be used to treat COVID-19 and provide new ideas for the discovery of small molecular compounds with potential therapeutic effects on novel COVID-19.
In late December 2019, an outbreak of pneumonia of unknown cause began in Wuhan, Hubei Province, China, spreading rapidly around the world [1]. Chinese researchers discovered a previously unknown betacoronavirus through the use of unbiased sequencing in samples from patients with pneumonia [2]. This coronavirus, named SARS-CoV-2, causes a disease called COVID-19 that can be transmitted from person to person [3,4]. COVID-19 may rapidly develop into acute respiratory distress syndrome (ARDS) and in some cases, lead to multiple organ dysfunction or death. In view of alarming levels of spread and severity, COVID-19 was declared a public health emergency of international concern on January 30, 2020 and situated as a pandemic on March 11, 2020 by WHO [5,6]. As of May 3, 2020, there have been more than 3.3 million reported cases and 230,000 deaths in more than 200 countries. Unfortunately, no drugs or vaccines have been approved for combating the virus [7]. Considering the growing threat of COVID-19 pandemic, it is essential to study the efficacy of existing antiviral drugs as well as Chinese herbal medicines against SARS-CoV-2. In this review, we summarized the epidemiological characteristics, pathogenesis, virus structure and targeting strategies of COVID-19, with emphasis on the re-purposing of clinically approved drugs and Chinese herbal medicines that may be used to treat COVID-19 and provide new ideas for the discovery of small molecular compounds with potential therapeutic effects on COVID-19.

1. Genome structure and pathogenesis of SARS-CoV-2

SARS-CoV-2 is a spherical, enveloped, single-stranded positive RNA virus with a diameter of 80 nm–160 nm and a genome size of 29.9 kb [8]. SARS-CoV-2 falls within the subgenus Sarbecovirus of the genus Betacoronavirus that shares about 79.6 % identity with genome of SARS-CoV [9,10]. The architecture of virions is composed of nucleic acid and nucleocapsid protein to form the helical nucleocapsid. Lipid envelope which is studded with structural protein including the membrane (M) glycoprotein, the envelope (E) protein, and the spike (S) glycoprotein [11].

Virus infection is initiated by the interaction between S protein and host cell surface receptors. The S protein would be cleaved by the cellular serine proteases TMPRSS2 into S1 and S2 subunits, which are responsible for receptor recognition and membrane fusion [12,13]. The C-terminal domain (CTD) of S1 specifically binds to host cell receptors angiotensin-converting enzyme 2 (ACE2) or CD147, which causes the conformational change of S2. Then two heptad repeats join in S2 forming an anti-parallel six-helix bundle that allows for the mixing of viral and cellular membranes, resulting in release of the viral genome into the cytoplasm subsequently [14,15]. After release, the viral genomic RNA begins to express. The replicase gene encodes two large ORFS, rep1a and rep1b, which express two co-terminal polyproteins, pp1a and pp1ab. They produce 16 unstructured proteins which assemble into the replicase–transcriptase complex (RTC). RTC creates an environment suitable for RNA synthesis and is ultimately responsible for RNA replication and transcription of the sub genome RNAs. After replication and sub genome RNA synthesis, the S, E and M viral structural proteins are translated and inserted into the endoplasmic reticulum (ER), subsequently moved into endoplasmic reticulum-Golgi intermediate compartment (ERGIC) [16]. There, N protein encapsulates viral genome buds into a membrane containing ERGIC to form mature viruses, which are transported to the cell surface in vesicles and released by exocytosis [17].

After SARS-CoV-2 infection, pathogenic T cells are rapidly activated to produce granulocyte macrophage colony stimulating factors, such as GM-CSF and IL-6 [18]. GM-CSF will further activate CD14+/CD16+ inflammatory monocytes to produce a large amount of IL-6 and other inflammatory factors by a positive feedback effect [19,20]. In addition, high levels of neutrophil extracellular traps may also contribute to cytokine release [21]. Ultimately, uncontrolled inflammatory responses may lead to shock and tissue damage in the heart, liver and kidney, as well as respiratory failure or multiple organ failure, causing death in patients with severe COVID-19 [22,23] (Fig. 1 ).

Fig. 1 : Life cycle of SARS-CoV-2 in host cells. (A) Structure of SARS-CoV-2. (B) Mechanism of SARS-CoV-2 infection.

2. Key targets and their roles in SARS-CoV-2 infection

Therapeutics with high specificity and efficacy is the ultimate goal of pathogenesis study, while target discovery is the foundation. Based on previous studies, spike protein, ACE2, TMPRSS2, 3CLpro, RdRp and PLpro are considered as major targets for antiviral drugs against SARS and other coronavirus infections [24]. Sharing high conservation of the catalytic site and homology with SARS-CoV [9,25], the above six proteins may be potential targets for the treatment of COVID-19. From the view of virus and cell fusion, Arbidol, a broad-spectrum antiviral drug, as a virus-host cell fusion inhibitor, can prevent virus from entering host cells to treat COVID-19 [26]. It has also been shown that SARS-CoV-2 depends on Spike proteins on the surface to entry into host cells by binding to Angiotensin-converting enzyme 2 (ACE2) receptors on the host cell surface [12]. ACE2 is the host cell surface receptor, which is the key to the initial stage of SARS-CoV-2 invasion into the host. Therefore, excess soluble forms of ACE2 or ACE2 inhibitors could be a possible methodology to treat COVID 19. In addition, Transmembrane Protease Serine 2 (TMPRSS2) can activate Spike protein and promote SARS-CoV-2 infection of host cells, which plays an important role in the process of SARS-CoV-2 infection of host cells [12]. The existing TMPRSS2 inhibitor Carmustat mesylate, bromhexine hydrochloride may also be an effective treatment for COVID-19 [12,27]. From the view of virus proteases, 3C-like protease (3CLpro) and Papain-like protease (PLpro) are two viral proteases responsible for cleaving viral peptides into functional units for virus replication and packaging in host cells. It has been shown that SARS-CoV-2 3CLpro inhibitors, baicalin and baicalein exhibit strong antiviral activity in cell-based systems [28]; 6-Mercaptopurine (6 M P) and 6-thioguanine (6 TG) are specific inhibitors of SARS-CoV and MERS-CoV papain, deubiquitinated and isg-depleted cysteine proteases [29,30], they may be reasonable candidates. From view of virus replication, Nsp12, an RNA-dependent RNA polymerase (RdRp), is an important enzyme of the coronavirus replication/transcription complex [31]. Currently, inhibitors targeting RdRp are mainly ribavirin, remdesivir, etc., and these drugs mainly compete with physiological nucleotides for the RdRp active site [32].

4. Chinese herbal medicines with the potential to inhibit COVID-19

Previously, we summarized small molecules currently used/planned to treat COVID-19, which may be an important short-term strategy for the treatment of COVID-19, but their efficacy and safety in COVID-19 need to be further confirmed by clinical trials. Drug development against COVID-19 appears to be crucial in the context of a rapidly evolving epidemic, however, the conventional development of new drugs is time-consuming with safety concern. Therefore, it seems unrealistic to synthesize new drugs and perform safety and toxicity tests over a short period of time. Antiviral therapy with Chinese herbal medicines have been recorded for a long time in Chinese history, and previous studies have shown that Chinese herbal medicines have great potential for preventing SARS transmission [105]. Given the low toxicity and availability of Chinese herbal medicines, screening active compounds targeting viral or host targets from Chinese herbal medicines may be a potential strategy for treating COVID-19. In this review, we summarized potential Chinese herbal medicines (Table 2 ) that may treat COVID-19 by targeting proteins such as Spike protein, ACE2, 3CLpro, PLpro and RdRp. We also predicted the binding affinities between these compounds and COVID-19 related targets by molecular docking, with a focus on six compounds: quercetin, andrographolide, glycyrrhizic acid, baicalin, patchouli alcohol, and luteolin. And the binding patterns of these six compounds to the key targets of SARS-CoV-2 are shown in Fig. 2 .

Table 2

Summary of potential Chinese herbal medicines against SARS-CoV-2.

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Fig. 2  The optimized binding patterns of ligands with key targets of SARS-CoV-2 by molecular docking, including (A) Andrographolide, (B) Baicalin, (C) Quercetin, (D) Glycyrrhizic acid, (E) Patchouli alcohol and (F) Luteolin.

4.1. Quercetin

Quercetin, a flavonoid compound, is widespread in fruit and vegetables. As a dietary source compound, quercetin exerts diverse biological activities including anti-inflammatory, anti-oxidant, anti-viral, anti-allergic, anti-cancer, mood-improving as well as vasoprotective [[106], [107], [108]]. Studies have found that quercetin exhibits antiviral properties against a variety of viruses, including Influenza A Virus (IAV) [108], Hepatitis C Virus (HCV) [109], Enterovirus 71 (EV71) [110], and SARS-CoV, etc [111,112]. It has been confirmed that quercetin showed a good inhibitory effect on SARS-CoV 3CLpro expressed in Pichia pastoris, with an inhibition rate of 82 % [111]. In addition, enzyme inhibition assays in vitro also showed that quercetin had inhibitory activity against SARS-CoV 3CLpro [112]. Since the 3CLpro sequence of SARS-CoV-2 is highly similar to that of SARS-CoV [10,25], we speculated that quercetin may also exhibit antiviral effects on SARS-CoV-2. However, it has not been documented whether quercetin inhibits SARS-CoV-2, so we docked quercetin to 3CLpro as well as other key targets, and the docking results showed that quercetin bound well to each target, with a binding energy of -5.6 kcal/mol to 3CLpro. Surprisingly, we found that quercetin bounds better to Spike protein, ACE2, RdRp and PLpro indicating good potential against SARS-CoV-2. In addition, it has a wide range of sources with relatively low cost, so it is worth testing its efficacy against SARS-CoV-2 infection.

4.2. Andrographolide

Andrographolide, the main active component isolated from the extract of the herb andrographis paniculata, has a wide range of biological activities including immunity regulation, anti-virus, anti-bacteria, anti-parasite, anti-tumor, and anti-hyperglycemia [113,114]. Previous studies have shown that andrographolide has a broad spectrum of antiviral properties, which inhibits various virus infections including influenza A virus (IAV) [115], human immunodeficiency virus (HIV) [116], Chikungunya virus (CHIKV) [117], dengue virus (DENV) [118,119], and Enterovirus D68 (EV-D68) [120]. Atchara Paemanee et al. suggested that andrographolide may exert broad-spectrum antiviral activity by interfering a variety of cellular pathways (including autophagy, unfolded protein response (UPR) pathway and oxidative stress, etc.). They further found the anti-dengue virus activity by acting on GRP78, a key regulator of unfolded protein response [119]. In addition, andrographolide exerts antiviral activity against H1N1 by inhibiting the activation of RLRs signaling pathways and thereby improving H1N1 virus-induced cell death [121]. To test the anti-viral activity against SARS-CoV-2, we docked andrographolide with key targets, and the results also showed that andrographolide bound well to the key targets including Spike protein, ACE2, 3CLpro, RdRp and PLpro, which indicated that andrographolide has potential efficacy against SARS-CoV-2. Moreover, Enmozhi, S. K. et al. proved andrographolide as a potential inhibitor of SARS-CoV-2 3CLpro through in silico studies [122]. Overall, as a plant-derived compound, andrographolide is widely distributed with low cytotoxicity, but its potent antiviral activity against a variety of viruses calls for further investigation.

4.3. Glycyrrhizic acid

Glycyrrhizic acid is a plant product isolated from the traditional Chinese medicine licorice (Chinese name: Gan Cao). Glycyrrhiza uralensis contains active ingredients such as thymol and carvacrol, which have significant antiviral and bactericidal effects [123]. A large number of studies have shown that licorice and its chemical components have protective effect on lung inflammation and damage, and it is a promising herbal medicine for treating SARS [124]. Cinatl J et al. compared the effects of conventional antiviral drugs ribavirin, 6-azouridine, pyrazofurin, mycophenolic acid, and glycyrrhizic acid on SARS-CoV, and the experimental results showed that glycyrrhizic acid had a better viral inhibitory effect than the other four drugs in inhibiting the viral adsorption and penetration [125]. Hoever G et al. also showed that glycyrrhizic acid has a good anti-SARS-CoV effect, while SARS-CoV-2 and SARS-CoV belong to different subclasses of coronaviruses with similar structures [126]. In addition, glycyrrhizic acid can promote IFN-γ production by T cells [127]. Recent studies have shown that SARS-CoV-2 and SARS-CoV have the same receptor ACE2, and glycyrrhizic acid can bind to this receptor, suggesting that glycyrrhizic acid may have therapeutic effects on SARS-CoV-2 [128]. To discuss whether glycyrrhizic acid has an anti-SARS-CoV-2 effect, we performed molecular docking of glycyrrhizic acid with the binding energy of glycyrrhizic acid and ACE2 -7.0 kcal/mol (As the shown in Table 2). At the same time, the binding energy of glycyrrhizic acid with other targets: 3CLpro, PLpro, RdRp and Spike is -6.9 kcal/mol, -7.3 kcal/mol, -7.2 kcal/mol, -6.5 kcal/mol, respectively. It can be seen that glycyrrhizic acid also has strong binding affinity to other targets. Given the antiviral effect of glycyrrhizic acid on SARS-CoV, and its potential interaction with ACE2, we speculated that glycyrrhizic acid may have potential to treat SARS-CoV-2. Moreover, glycyrrhizic acid plays an important role in inhibiting immune hyperactivation and cytokine storm factor development [129], therefore, we believe it is worth testing its efficacy against SARS-CoV-2 infection.

4.4. Baicalin

Baicalin, a component of Scutellaria baicalensis Georgi (Chinese name: Huang Qin), has a wide range of therapeutic effects, including sensitization and anti-apoptosis [130,131]. Chen et al. have demonstrated the antiviral activity of baicalin against SARS coronavirus, with an EC50 value of 12.5 μg/mL at 48 h, and the activity tended to decrease with incubation time beyond 48 h [132]. Due to the similarities between SARS-CoV-2 and SARS-CoV, it can be speculated that baicalin may also have an antiviral effect on SARS-CoV-2. In addition, Deng et al. used UV spectrophotometry to determine angiotensin-converting enzyme inhibitory activity and found that baicalin could inhibit ACE in vitro, with an IC50 value of 2.24 mM [133]. Hansen Chen et al. used molecular docking technology to find that baicalin may have a strong binding effect with ACE2, and the possible binding sites are ASN-149, ARG-273, HIS-505 [128]. Haixia Su et al. showed that baicalin, as a non-covalent inhibitor of SARS-CoV-2 3CLpro, has high ligand binding efficiency and specific binding to proteases by ITC map, native electrospray ionization mass spectrometry (ESI-MS) and its chemical structure [28]. At the same time, we used molecular docking to study the docking of baicalin to other key targets of SARS-CoV-2, in which the binding energy of baicalin to the target PLpro was -8.5 kcal/mol. The results of docking showed that baicalin bounds strongly to other targets of SARS-CoV-2 (Table 2). Therefore, it can be reasonably speculated that baicalin is one of the potential drugs for COVID-19 treatment. In view of the low toxic effect of baicalin, its effect against SARS-CoV-2 warrants further study.

4.5. Patchouli alcohol

Patchouli alcohol (PA), a tricyclic sesquiterpene compound extracted from the traditional Chinese medicine patchouli, has a wide range of pharmacological and biological effects including antiviral, immunomodulatory, anti-inflammatory, antioxidative, and antitumor [134]. PA has been found to have anti-influenza A (IAV) effect in vitro, while H1N1 virus is the most sensitive to PA [135]. In addition, Yunjia Yu et al. found that intracellular PI3K/Akt and ERK/MAPK signaling pathways may be involved in the anti-IAV effect of PA and PA significantly inhibits the in vitro proliferation of different IAV, suggesting that PA may block IAV infection by directly killing viral particles and interfering with some early stages after viral adsorption [136]. Another study showed that PA also has an effect against influenza virus (IFV) in vivo and enhances protection against IFV infection in mice by enhancing host immune responses and attenuating systemic and pulmonary inflammatory responses [137]. To investigate the anti-SARS-CoV-2 activity of PA, we investigated the possibility of PA binding to SARS-CoV-2 related targets using molecular docking (Table 2). The docking results showed that the binding effect of PA and Rdrp was satisfactory, which provided some support for the antiviral effect of PA. The above study results showed that patchouli alcohol had antiviral effect and also modulated the levels of inflammatory cytokines, suggesting that PA may be a novel and effective antiviral and anti-inflammatory drug for COVID-19.

4.6. Luteolin

Luteolin, a natural flavonoid extracted from Chinese herbal medicine, displays multiple biological activities, including anti-inflammatory, anti-cancer, antioxidant, antiviral, and heart protective [138]. It was reported that luteolin can interfere with the virus in early virus life cycle, to a certain extent, block the absorption and internalization of influenza virus, thereby inhibited the replication of IAV [139]. The above experiments suggested that luteolin is a potential antiviral drug that inhibits viral replication by regulating host proteins. In addition, Minhua Peng et al. confirmed luteolin inhibited the dengue virus NS2B/NS3 protease activity by analyzing the nucleotide sequence of the luteolin-resistant escape mutant [140]. It also has been documented luteolin has an anti-Epstein-Barr virus (EBV) effect, and in immunoblot analysis, 20 μg/mL of luteolin showed a significant inhibitory effect on EBV lytic cycle [141]. Another study showed that luteolin extracted from Torreya Nucifera is an effective SARS-CoV 3CLpro inhibitor [112]. To interrogate the anti-SARS-CoV-2 effect of luteolin, we performed molecular docking of luteolin to key targets of SARS-CoV-2. The docking results showed that luteolin bound well to the key target of SARS-CoV-2. Among them, the binding energy of luteolin to ACE2 was -7.1 kcal/mol (Table 2). Taken together, luteolin has a good antiviral effect, which suggests that luteolin may be a potential drug for the treatment of COVID-19.

The results of molecular docking are shown in Table 2. From the target point of view, the binding effect of ACE2 and PLpro with these natural compounds was more prominent; while from the natural compounds, the lowest binding energy was -9.0 kcal/mol for Cryptotanshinone and PLpro, while the highest was -4.3 kcal/mol for Lignan and 3CLpro, that is to say, the range of binding energy was from -9.0 kcal/mol to -4.3 kcal/mol, which indicated that the natural compounds had a good binding effect with the target. Our aim of docking was to select natural compounds with high potential efficacy against SARS-CoV-2, but it should be pointed out that these compounds cannot be considered to treat COVID-19 only by such a screen which is aimed to provide priority to focus. Furthermore, the 3D structure of the targets we used were based on the reported gene sequences. If the virus mutates during transmission, new screening is recommended. In conclusion, our review summarizes more than a dozen of natural compounds classified as antiviral/pneumonic protectors, which may directly inhibit SARS-CoV-2. However, their actual effect in the treatment of COVID-19 needs to be verified by further studies.

5.Comparison and combination therapy of clinically approved drugs and Chinese herbal medicines

Developing new application of FDA approved drugs is the most effective strategy for sudden new diseases and will rapidly alleviate the current epidemic situation [153]. Compared with new drugs, existing antiviral drugs have the advantages of safety, pharmacokinetic characteristics, clear clinical adverse reactions. And by further verifying the effectiveness of drugs that have completed at least clinical phase I can save preclinical and partial clinical study time and shorten the time cost of drug research and development. However, because existing antiviral drugs are not designed for SARS-CoV-2, they may not be ideal in antiviral efficacy and require larger doses, which may bring more serious side effects.

From the occurrence of the epidemic to date, traditional Chinese medicines also played an extremely important role. Guided by the theory of traditional Chinese medicine, exerting the advantages of overall regulation of traditional Chinese medicine is an important method for the clinical treatment of COVID-19. At present, Qingfei Paidu Decoction is recommended for the treatment of clinically confirmed cases according to Guideline for the Diagnosis and Treatment of Novel Coronavirus (SARS-CoV-2) Pneumonia (On Trials, the Seventh Edition) in China [39]. A study including 98 patients with COVID-19 showed that Qingfei Paidu Decoction has a good clinical effect for the treatment of COVID-19, it can significantly improve the abnormal laboratory test indicators and clinical symptoms of patients, reduce the adverse reactions of patients, and effectively improve the therapeutic effect [154]. In addition, Lianhua Qingwen was also demonstrated to significantly inhibit SARS-COV-2 replication in Vero E6 cells at the mRNA level as well as markedly reduce the production of pro-inflammatory cytokines, suggesting that Lianhua Qingwen may have a potential inhibitory effect on the cytokine storm induced by SARS-COV-2 [155]. At present, symptomatic and supportive therapy is still the key to clinical treatment. Therefore, traditional Chinese medicines have both antiviral and symptom-relieving effects may lead to better therapeutic effects.

At present, western medicine treatment is mainly based on the principles of symptomatic treatment, prevention of complications, treatment of underlying diseases, and prevention of infection [39], while traditional Chinese medicines play an important role in relieving the symptoms of patients and delaying or reducing the development of mild diseases into severe diseases [156], and may also play a role in reducing the side effects of western medicine, especially in the recovery of pulmonary function [157]. Both Chinese herbal medicine and approved western medicine have their own advantages in the treatment of COVID-19. In the course of COVID-19’s treatment, the combination of Chinese herbal medicine and approved western medicine has shown obvious effect, which is of great value in alleviating the early clinical symptoms of patients and reducing the incidence of patients from mild to severe then to intensive care [158]. The combination of nefenavir and sinomenine significantly reduced the amount of virus accumulation and shortened the time of virus clearance compared with single use of nefenavir and sinomenine [159]. In short, the combination of Chinese herbal medicine and approved western medicine is worth thinking about in the future treatment of COVID-19.

 

6. Conclusions and future prospects

COVID-19 poses a great threat to global health and safety. It is an urgent task for us to control the spread of the epidemic and reduce the mortality rate as soon as possible. But so far, the specific mechanism of the virus is still unclear, and no specific drug has been developed for the virus. At present, it is important to control the source of infection, cut off the route of transmission, and make use of existing drugs and means to actively control the progress of the disease. Efforts should also be made to develop specific drugs, promote vaccine research and development, reduce disease morbidity and mortality, and better protect the lives of the people.

At present, the potential therapeutic agents used in COVID-19 come from previous experience in treating SARS, MERS or other new influenza viruses. As broad-spectrum antiviral drugs have long been approved on the market to treat different viral infections, their metabolic characteristics, dosage, potential efficacy and side effects are clear. Re-purposing of clinically approved drugs may be an important short-term strategy for the treatment of novel coronavirus. But the disadvantage is that these treatments are too “broad-spectrum” to specifically treat COVID-19. In addition, its side effects can not be underestimated. A number of clinical trials are under way to evaluate the effectiveness of other treatment options. Active symptomatic support is still the key to treatment. Although stem cells, monoclonal antibodies, polypeptides, interferon or plasma from recovered patients have been shown to be effective in treating COVID-19 patients, their safeties are still being evaluated and the efficacy remains to be further confirmed.

Except the some undergoing small molecules, this paper also focuses on the most promising compounds in traditional Chinese medicine in recent years, which can be used as effective antiviral drugs for the treatment of diseases caused by SARS-CoV-2 based on in vitro and in vivo studies. In addition, computer molecular docking shows that these monomers have good binding ability to COVID-19 virus and host targets. The low toxicity and availability of active compounds of traditional Chinese medicine should be used as potential drug candidates for COVID-19 treatment.

This review also has limitations. The large and rapidly published literature on COVID-19’s treatment means that the findings and recommendations are constantly evolving as new evidence arises. It is not uncommon that drugs that proved effective at an early stage based on small-scale clinical trials later turned out to be ineffective. We look forward to the cooperation of all scientists around the world to develop effective drugs to treat current and future potential SARS-CoV-2 infections to control the further spread of the epidemic.

Disclosures

All authors have read and approved the final submission.

Declaration of Competing Interest

There is no conflict of interest associated with this article.

Acknowledgments

This project was supported by the PhD Start-up Fund of Guangdong Medical University (B2019016); Administration of Traditional Chinese Medicine of Guangdong Province (20201180); Science and Technology Special Project of Zhanjiang (2019A01009); Educational Commission of Guangdong Province (2020KZDZX1102, 2020KZDZX1100).

References

  1. Lu H., Stratton C.W., Tang Y.W. Outbreak of pneumonia of unknown etiology in Wuhan, China: the mystery and the miracle. J. Med. Virol. 2020;92:401–402. doi: 10.1002/jmv.25678. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Zhu N., Zhang D., Wang W., Li X., Yang B., Song J. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 2020;382:727–733. doi: 10.1056/NEJMoa2001017. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Chan J.F., Yuan S., Kok K.H., To K.K., Chu H., Yang J. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020;395:514–523. doi: 10.1016/S0140-6736(20)30154-9. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. WHO . 2020. WHO Director-General’s Remarks at the Media Briefing on 2019-nCoV on 11 February 2020.https://www.who.int/dg/speeches/detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020(Accessed 27 March 2020) [Google Scholar] 
  1. WHO . 2020. Virtual Press Conference on COVID-19 – 11 March 2020.https://www.who.int/docs/default-source/coronaviruse/transcripts/who-audio-emergencies-coronavirus-press-conference-full-and-final-11mar2020.pdf?sfvrsn=cb432bb3_2(Accessed 27 March 2020) [Google Scholar] 
  1. WHO . 2020. Statement on the Second Meeting of the International Health Regulations (2005) Emergency Committee Regarding the Outbreak of Novel Coronavirus (2019-nCoV)https://www.who.int/news-room/detail/30-01-2020-statement-on-the-second-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-outbreak-of-novel-coronavirus-(2019-ncov)(Accessed 28 April 2020) [Google Scholar] 
  1. Patel A., Jernigan D.B. Initial public health response and interim clinical guidance for the 2019 novel coronavirus outbreak - United States, December 31, 2019-February 4, 2020. MMWR Morb. Mortal. Wkly. Rep. 2020;69:140–146. doi: 10.15585/mmwr.mm6905e1. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Liu C., Yang Y., Gao Y., Shen C., Ju B., Liu C. Viral architecture of SARS-CoV-2 with post-fusion spike revealed by Cryo-EM. bioRxiv. 2020 doi: 10.1101/2020.03.02.972927. 2020.03.02.972927. [CrossRef] [Google Scholar] 
  1. Zhou P., Yang X.L., Wang X.G., Hu B., Zhang L., Zhang W. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–273. doi: 10.1038/s41586-020-2012-7. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Lu R., Zhao X., Li J., Niu P., Yang B., Wu H. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395:565–574. doi: 10.1016/S0140-6736(20)30251-8. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  1. Deng X., Baker S.C. 2014. Coronaviruses: Molecular Biology, Reference Module in Biomedical Sciences. [CrossRef] [Google Scholar] 
  1. Hoffmann M., Kleine-Weber H., Schroeder S., Kruger N., Herrler T., Erichsen S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;181:271–280. doi: 10.1016/j.cell.2020.02.052. e8. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Walls A.C., Park Y.J., Tortorici M.A., Wall A., McGuire A.T., Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020;181:281–292. doi: 10.1016/j.cell.2020.02.058. e6. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Wang Q., Zhang Y., Wu L., Niu S., Song C., Zhang Z. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell. 2020 doi: 10.1016/j.cell.2020.03.045. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Wang K., Chen W., Zhou Y., Lian J., Zhang Z., Du P. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein. bioRxiv. 2020 doi: 10.1101/2020.03.14.988345. 2020.03.14.988345. [CrossRef] [Google Scholar] 
  1. Knoops K., Kikkert M., Worm S.H., Zevenhoven-Dobbe J.C., van der Meer Y., Koster A.J. SARS-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum. PLoS Biol. 2008;6:e226. doi: 10.1371/journal.pbio.0060226. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Fehr A.R., Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol. Biol. 2015;1282:1–23. doi: 10.1007/978-1-4939-2438-7_1. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Wang X., Xu W., Hu G., Xia S., Sun Z., Liu Z. SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion. Cell. Mol. Immunol. 2020 doi: 10.1038/s41423-020-0424-9. [PMC free article] [PubMed] [CrossRef] [Google Scholar] Retracted 
  1. Shimabukuro-Vornhagen A., Godel P., Subklewe M., Stemmler H.J., Schlosser H.A., Schlaak M. Cytokine release syndrome. J. Immunother. Cancer. 2018;6:56. doi: 10.1186/s40425-018-0343-9. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Thevarajan I., Nguyen T., Koutsakos M., Druce J., Caly L., van de Sandt C.E. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nat. Med. 2020;26:453–455. doi: 10.1038/s41591-020-0819-2. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Zuo Y., Yalavarthi S., Shi H., Gockman K., Zuo M., Madison J.A. Neutrophil extracellular traps (NETs) as markers of disease severity in COVID-19. medRxiv. 2020 doi: 10.1101/2020.04.09.20059626. 2020.04.09.20059626. [CrossRef] [Google Scholar] 
  1. Cao X. COVID-19: immunopathology and its implications for therapy. Nat. Rev. Immunol. 2020 doi: 10.1038/s41577-020-0308-3. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Schett G., Sticherling M., Neurath M.F. COVID-19: risk for cytokine targeting in chronic inflammatory diseases? Nat. Rev. Immunol. 2020 doi: 10.1038/s41577-020-0312-7. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Zumla A., Chan J.F., Azhar E.I., Hui D.S., Yuen K.Y. Coronaviruses - drug discovery and therapeutic options. Nat. Rev. Drug Discov. 2016;15:327–347. doi: 10.1038/nrd.2015.37. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Morse J.S., Lalonde T., Xu S., Liu W.R. Learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-nCoV. Chembiochem. 2020;21:730–738. doi: 10.1002/cbic.202000047. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Kadam R.U., Wilson I.A. Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol. Proc Natl Acad Sci U S A. 2017;114:206–214. doi: 10.1073/pnas.1617020114. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Lucas J.M., Heinlein C., Kim T., Hernandez S.A., Malik M.S., True L.D. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer Discov. 2014;4:1310–1325. doi: 10.1158/2159-8290.CD-13-1010. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Su H., Yao S., Zhao W., Li M., Liu J., Shang W. Discovery of baicalin and baicalein as novel, natural product inhibitors of SARS-CoV-2 3CL protease in vitro. bioRxiv. 2020 doi: 10.1101/2020.04.13.038687. 2020.04.13.038687. [CrossRef] [Google Scholar] 
  1. Chen X., Chou C.Y., Chang G.G. Thiopurine analogue inhibitors of severe acute respiratory syndrome-coronavirus papain-like protease, a deubiquitinating and deISGylating enzyme. Antivir. Chem. Chemother. 2009;19:151–156. doi: 10.1177/095632020901900402. [PubMed] [CrossRef] [Google Scholar] 
  1. Cheng K.W., Cheng S.C., Chen W.Y., Lin M.H., Chuang S.J., Cheng I.H. Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus. Antiviral Res. 2015;115:9–16. doi: 10.1016/j.antiviral.2014.12.011. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Gorbalenya A.E., Pringle F.M., Zeddam J.L., Luke B.T., Cameron C.E., Kalmakoff J. The palm subdomain-based active site is internally permuted in viral RNA-dependent RNA polymerases of an ancient lineage. J. Mol. Biol. 2002;324:47–62. doi: 10.1016/s0022-2836(02)01033-1. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Wang M., Cao R., Zhang L., Yang X., Liu J., Xu M. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30:269–271. doi: 10.1038/s41422-020-0282-0. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

 

  1. Sanders J.M., Monogue M.L., Jodlowski T.Z., Cutrell J.B. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. JAMA. 2020 doi: 10.1001/jama.2020.6019. [PubMed] [CrossRef] [Google Scholar] 
  1. Savarino A., Boelaert J.R., Cassone A., Majori G., Cauda R. Effects of chloroquine on viral infections: an old drug against today’s diseases. Lancet Infect. Dis. 2003;3:722–727. doi: 10.1016/S1473-3099(03)00806-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Al-Bari M. Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacol. Res. Perspect. 2017;5 doi: 10.1002/prp2.293. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Zhou D., Dai S.M., Tong Q. COVID-19: a recommendation to examine the effect of hydroxychloroquine in preventing infection and progression. J. Antimicrob. Chemother. 2020 doi: 10.1093/jac/dkaa114. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Gao J., Tian Z., Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci. Trends. 2020;14:72–73. doi: 10.5582/bst.2020.01047. [PubMed] [CrossRef] [Google Scholar] 
  1. Yao X., Ye F., Zhang M., Cui C., Huang B., Niu P. 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) Clin. Infect. Dis. 2020 doi: 10.1093/cid/ciaa237. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. National Health Commission of the People’s Republic of China . 2020. Guideline for the Diagnosis and Treatment of Novel Coronavirus (SARS-CoV-2) Pneumonia (On Trials, the Seventh Edition)http://www.nhc.gov.cn/yzygj/s7653p/202003/46c9294a7dfe4cef80dc7f5912eb1989/files/ce3e6945832a438eaae415350a8ce964.pdf(Accessed 28 April 2020) [Google Scholar] 
  1. The multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia. Chin J Tuberc Respir Dis. 2020;43:185–188. doi: 10.3760/cma.j.issn.1001-0939.2020.03.009. [PubMed] [CrossRef] [Google Scholar] 
  1. Chen Z., Hu J., Zhang Z., Jiang S., Han S., Yan D. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. 2020 doi: 10.1101/2020.03.22.20040758. 2020.03.22.20040758. [CrossRef] [Google Scholar] 
  1. Gautret P., Lagier J.C., Parola P., Hoang V.T., Meddeb L., Mailhe M. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int. J. Antimicrob. Agents. 2020 doi: 10.1016/j.ijantimicag.2020.105949. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. 2020. Statement on IJAA Paper.https://www.isac.world/news-and-publications/official-isac-statement(Accessed 28 April 2020) [Google Scholar] 
  1. Borba M., Val F., Sampaio V.S., Alexandre M., Melo G.C., Brito M. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open. 2020;3 doi: 10.1001/jamanetworkopen.2020.8857. [PubMed] [CrossRef] [Google Scholar] 
  1. Chorin E., Dai M., Shulman E., Wadhwani L., Bar-Cohen R., Barbhaiya C. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nat. Med. 2020 doi: 10.1038/s41591-020-0888-2. [PubMed] [CrossRef] [Google Scholar] 
  1. Colson P., Rolain J.M., Lagier J.C., Brouqui P., Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int. J. Antimicrob. Agents. 2020;55 doi: 10.1016/j.ijantimicag.2020.105932. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. FDA . 2020. FDA Cautions Against Use of Hydroxychloroquine or Chloroquine for COVID-19 Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems.https://www.fda.gov/drugs/drug-safety-and-availability/fda-cautions-against-use-hydroxychloroquine-or-chloroquine-covid-19-outside-hospital-setting-or(Accessed 28 April 2020) [Google Scholar] 
  1. Fihn S.D., Perencevich E., Bradley S.M. Caution needed on the use of chloroquine and hydroxychloroquine for coronavirus disease 2019. JAMA Netw Open. 2020;3 doi: 10.1001/jamanetworkopen.2020.9035. [PubMed] [CrossRef] [Google Scholar] 
  1. Mulangu S., Dodd L.E., Davey R.J., Tshiani M.O., Proschan M., Mukadi D. A randomized, controlled trial of ebola virus disease therapeutics. N. Engl. J. Med. 2019;381:2293–2303. doi: 10.1056/NEJMoa1910993. [PubMed] [CrossRef] [Google Scholar] 
  1. Agostini M.L., Andres E.L., Sims A.C., Graham R.L., Sheahan T.P., Lu X. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. Mbio. 2018;9 doi: 10.1128/mBio.00221-18. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Sheahan T.P., Sims A.C., Graham R.L., Menachery V.D., Gralinski L.E., Case J.B. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci. Transl. Med. 2017;9 doi: 10.1126/scitranslmed.aal3653. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Sheahan T.P., Sims A.C., Leist S.R., Schäfer A., Won J., Brown A.J. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat. Commun. 2020;11:222–314. doi: 10.1038/s41467-019-13940-6. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. de Wilde A.H., Snijder E.J., Kikkert M., van Hemert M.J. Host factors in coronavirus replication. Curr. Top. Microbiol. Immunol. 2018;419:1–42. doi: 10.1007/82_2017_25. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Holshue M.L., DeBolt C., Lindquist S., Lofy K.H., Wiesman J., Bruce H. First case of 2019 novel coronavirus in the United States. N. Engl. J. Med. 2020;382:929–936. doi: 10.1056/NEJMoa2001191. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Wang Y., Zhang D., Du G., Du R., Zhao J., Jin Y. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020 doi: 10.1016/S0140-6736(20)31022-9. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Grein J., Ohmagari N., Shin D., Diaz G., Asperges E., Castagna A. Compassionate use of remdesivir for patients with severe Covid-19. N. Engl. J. Med. 2020 doi: 10.1056/NEJMoa2007016. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Williamson B.N., Feldmann F., Schwarz B., Meade-White K., Porter D.P., Schulz J. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. bioRxiv. 2020 doi: 10.1101/2020.04.15.043166. 2020.04.15.043166. [PubMed] [CrossRef] [Google Scholar] 
  1. Al-Tawfiq J.A., Al-Homoud A.H., Memish Z.A. Remdesivir as a possible therapeutic option for the COVID-19. Travel Med. Infect. Dis. 2020 doi: 10.1016/j.tmaid.2020.101615. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. de Wilde A.H., Jochmans D., Posthuma C.C., Zevenhoven-Dobbe J.C., van Nieuwkoop S., Bestebroer T.M. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob. Agents Chemother. 2014;58:4875–4884. doi: 10.1128/AAC.03011-14. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Huang X., Xu Y., Yang Q., Chen J., Zhang T., Li Z. Efficacy and biological safety of lopinavir/ritonavir based anti-retroviral therapy in HIV-1-infected patients: a meta-analysis of randomized controlled trials. Sci. Rep. 2015;5:8528. doi: 10.1038/srep08528. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Chu C.M. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax. 2004;59:252–256. doi: 10.1136/thorax.2003.012658. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Arabi Y.M., Alothman A., Balkhy H.H., Al-Dawood A., AlJohani S., Al H.S. Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-beta1b (MIRACLE trial): study protocol for a randomized controlled trial. Trials. 2018;19:81. doi: 10.1186/s13063-017-2427-0. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Mangum E.M., Graham K.K. Lopinavir-Ritonavir: a new protease inhibitor. Pharmacotherapy. 2001;21:1352–1363. doi: 10.1592/phco.21.17.1352.34419. [PubMed] [CrossRef] [Google Scholar] 
  1. Lin S., Shen R., He J., Li X., Guo X. Molecular modeling evaluation of the binding effect of ritonavir, Lopinavir and darunavir to severe acute respiratory syndrome coronavirus 2 proteases. bioRxiv. 2020 doi: 10.1101/2020.01.31.929695. 2020.01.31.929695. [CrossRef] [Google Scholar] 
  1. Liu F., Xu A., Zhang Y., Xuan W., Yan T., Pan K. Patients of COVID-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression. Int. J. Infect. Dis. 2020 doi: 10.1016/j.ijid.2020.03.013. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Lim J., Jeon S., Shin H.Y., Kim M.J., Seong Y.M., Lee W.J. Case of the index patient who caused tertiary transmission of COVID-19 infection in Korea: the application of Lopinavir/Ritonavir for the treatment of COVID-19 infected pneumonia monitored by quantitative RT-PCR. J. Korean Med. Sci. 2020;35:e79. doi: 10.3346/jkms.2020.35.e79. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Deng L., Li C., Zeng Q., Liu X., Li X., Zhang H. Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: a retrospective cohort study. J. Infect. 2020 doi: 10.1016/j.jinf.2020.03.002. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Fan Z., Chen L., Li J., Cheng X., Jingmao Y., Tian C. Clinical features of COVID-19-Related liver damage. Clin. Gastroenterol. Hepatol. 2020 doi: 10.1016/j.cgh.2020.04.002. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Cao B., Wang Y., Wen D., Liu W., Wang J., Fan G. A trial of Lopinavir-Ritonavir in adults hospitalized with severe Covid-19. N. Engl. J. Med. 2020 doi: 10.1056/NEJMoa2001282. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Study for the efficacy of chloroquine in patients with novel coronavirus pneumonia (COVID-19). http://www.chictr.org.cn/showprojen.aspx?proj=48968. 2020 (Accessed 1 May 2020).
  2. 2020. A Randomised, Open, Controlled Trial for darunavir/cobicistat or Lopinavir/ritonavir Combined With Thymosin a1 in the Treatment of Novel Coronavirus Pneumonia (COVID-19)http://www.chictr.org.cn/showprojen.aspx?proj=48992(Accessed 1 May 2020) [Google Scholar] 
  1. Furuta Y., Komeno T., Nakamura T. Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 2017;93:449–463. doi: 10.2183/pjab.93.027. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Chen C., Zhang Y., Huang J., Yin P., Cheng Z., Wu J. Favipiravir versus arbidol for COVID-19: a randomized clinical trial. medRxiv. 2020 doi: 10.1101/2020.03.17.20037432. 2020.03.17.20037432. [CrossRef] [Google Scholar]
  2. Sheahan T.P., Sims A.C., Zhou S., Graham R.L., Pruijssers A.J., Agostini M.L. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci. Transl. Med. 2020;12 doi: 10.1126/scitranslmed.abb5883. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. 2020. FDA Clears the Way for Ridgeback Biotherapeutics to Begin Human Testing of a Promising Potential Treatment for COVID-19.https://www.prnewswire.com/news-releases/fda-clears-the-way-for-ridgeback-biotherapeutics-to-begin-human-testing-of-a-promising-potential-treatment-for-covid-19-301036307.html(Accessed 1 May 2020) [Google Scholar] 
  1. Richardson P., Griffin I., Tucker C., Smith D., Oechsle O., Phelan A. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020;395:e30–e31. doi: 10.1016/S0140-6736(20)30304-4. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Zhu L., Xu X., Ma K., Yang J., Guan H., Chen S. Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression. Am. J. Transplant. 2020 doi: 10.1111/ajt.15869. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. 2020. Effectiveness of Glucocorticoid Therapy in Patients With Severe Novel Coronavirus Pneumonia: a Randomized Controlled Trial.http://www.chictr.org.cn/showprojen.aspx?proj=48777(Accessed 1 May 2020) [Google Scholar] 
  1. Tang N., Bai H., Chen X., Gong J., Li D., Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J. Thromb. Haemost. 2020;18:1094–1099. doi: 10.1111/jth.14817. [PubMed] [CrossRef] [Google Scholar] 
  1. Mycroft-West C.J., Su D., Elli S., Li Y., Guimond S.E., Miller G.J. The 2019 coronavirus (SARS-CoV-2) surface protein (Spike) S1 Receptor Binding Domain undergoes conformational change upon heparin binding. bioRxiv. 2020 doi: 10.1101/2020.02.29.971093. 2020.02.29.971093. [CrossRef] [Google Scholar] 
  1. Te V.A., van den Worm S.H., Sims A.C., Baric R.S., Snijder E.J., van Hemert M.J. Zn(2+) inhibits coronavirus and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. PLoS Pathog. 2010;6 doi: 10.1371/journal.ppat.1001176. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Guan W.J., Ni Z.Y., Hu Y., Liang W.H., Ou C.Q., He J.X. Clinical Characteristics of Coronavirus Disease 2019 in China. N. Engl. J. Med. 2020;382:1708–1720. doi: 10.1056/NEJMoa2002032. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Lu H. Drug treatment options for the 2019-new coronavirus (2019-nCoV) Biosci. Trends. 2020;14:69–71. doi: 10.5582/bst.2020.01020. [PubMed] [CrossRef] [Google Scholar] 
  1. 2020. Clinical Study of Arbidol Hydrochloride Tablets in the Treatment of Novel Coronavirus Pneumonia (COVID-19)http://www.chictr.org.cn/showprojen.aspx?proj=49165(Accessed 1 May 2020) [Google Scholar] 
  1. Talwani R., Temesgen Z. Doravirine: a new non-nucleoside reverse transcriptase inhibitor for the treatment of HIV infection. Drugs Today. 2020;56:113–124. doi: 10.1358/dot.2020.56.2.3109966. [PubMed] [CrossRef] [Google Scholar] 
  1. Gubareva L., Mohan T. Antivirals targeting the neuraminidase. Csh Perspect Med. 2020 doi: 10.1101/cshperspect.a038455. [PubMed] [CrossRef] [Google Scholar] 
  1. Wang D., Hu B., Hu C., Zhu F., Liu X., Zhang J. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–Infected pneumonia in Wuhan, China. JAMA. 2020;323:1061. doi: 10.1001/jama.2020.1585. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. 2020. A Real-world Study for lopinavir/ritonavir (LPV/r) and Emtritabine (FTC) / Tenofovir Alafenamide Fumarate Tablets (TAF) Regimen in the Treatment of Novel Coronavirus Pneumonia (COVID-19)http://www.chictr.org.cn/showprojen.aspx?proj=48919(Accessed 1 May 2020) [Google Scholar] 
  1. Fung H.B., Stone E.A., Piacenti F.J. Tenofovir disoproxil fumarate: a nucleotide reverse transcriptase inhibitor for the treatment of HIV infection. Clin. Ther. 2002;24:1515–1548. doi: 10.1016/s0149-2918(02)80058-3. [PubMed] [CrossRef] [Google Scholar] 
  1. 2020. Randomized, Open-label, Controlled Trial for Evaluating of the Efficacy and Safety of Baloxavir Marboxil, Favipiravir, and Lopinavir-ritonavir in the Treatment of Novel Coronavirus Pneumonia (COVID-19) Patients.http://www.chictr.org.cn/showprojen.aspx?proj=49015(Accessed 1 May 2020) [Google Scholar] 
  1. Hayden F.G., Sugaya N., Hirotsu N., Lee N., de Jong M.D., Hurt A.C. Baloxavir Marboxil for uncomplicated influenza in adults and adolescents. New England J. Med. Surg. Collat. Branches Sci. 2018;379:913–923. doi: 10.1056/NEJMoa1716197. [PubMed] [CrossRef] [Google Scholar] 
  1. 2020. An Open, Controlled Clinical Trial for Evaluation of Ganovo Combined With Ritonavir and Integrated Traditional Chinese and Western Medicine in the Treatment of Novel Coronavirus Infection (COVID-19)http://www.chictr.org.cn/showprojen.aspx?proj=49748(Accessed 1 May 2020) [Google Scholar] 
  1. Rong L., Guedj J., Dahari H., Coffield D.J., Levi M., Smith P. Analysis of hepatitis C virus decline during treatment with the protease inhibitor danoprevir using a multiscale model. PLoS Comput. Biol. 2013;9 doi: 10.1371/journal.pcbi.1002959. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. 2020. Multicenter Study for the Treatment of Dipyridamole With Novel Coronavirus Pneumonia (COVID-19)http://www.chictr.org.cn/showprojen.aspx?proj=49864(accessed 1 May 2020) [Google Scholar] 
  1. Liu X., Li Z., Liu S., Chen Z., Zhao Z., Huang Y. Therapeutic effects of dipyridamole on COVID-19 patients with coagulation dysfunction. medRxiv. 2020 doi: 10.1101/2020.02.27.20027557. 2020.02.27.20027557. [CrossRef] [Google Scholar] 
  1. 2020. Fingolimod in COVID-19.https://clinicaltrials.gov/ct2/show/NCT04280588(Accessed 1 May 2020) [Google Scholar] 
  1. 2020. Losartan for Patients With COVID-19 Not Requiring Hospitalization.https://clinicaltrials.gov/ct2/show/NCT04311177(Accessed) [Google Scholar] 
  1. Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Develop Res. 2020 doi: 10.1002/ddr.21656. n/a. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Lane J.C.E., Weaver J., Kostka K., Duarte-Salles T., Abrahao M.T.F., Alghoul H. Safety of hydroxychloroquine, alone and in combination with azithromycin, in light of rapid wide-spread use for COVID-19: a multinational, network cohort and self-controlled case series study. medRxiv. 2020 doi: 10.1101/2020.04.08.20054551. 2020.04.08.20054551. [CrossRef] [Google Scholar] 
  1. 2020. Comparative Effectiveness and Safety of Ribavirin Plus Interferon-alpha, lopinavir/ritonavir Plus Interferon-alpha and Ribavirin Plus lopinavir/ritonavir Plus Interferon-alphain in Patients With Mild to Moderate Novel Coronavirus Pneumonia.http://www.chictr.org.cn/showprojen.aspx?proj=48782(Accessed 1 May 2020) [PMC free article] [PubMed] [Google Scholar] 
  1. Arabi Y.M., Shalhoub S., Mandourah Y., Al-Hameed F., Al-Omari A., Al Q.E. Ribavirin and interferon therapy for critically ill patients with middle east respiratory syndrome: a multicenter observational study. Clin. Infect. Dis. 2020;70:1837–1844. doi: 10.1093/cid/ciz544. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. 2020. The Efficacy and Safety of Triazavirin for 2019 Novel Coronary Pneumonia (COVID-19): a Multicenter, Randomized, Double Blinded, Placebo-controlled Trial.http://www.chictr.org.cn/showprojen.aspx?proj=49723(Accessed 1 May 2020) [Google Scholar] 
  1. 2020. Clinical Study of Novel NLRP Inflammasome Inhibitor (Tranilast) in the Treatment of Novel Coronavirus Pneumonia (COVID-19)http://www.chictr.org.cn/showprojen.aspx?proj=49738(Accessed 1 May 2020) [Google Scholar] 
  1. 2020. Multi-Center Clinical Study on the Treatment of Patients With Novel Coronavirus Pneumonia (COVID-19) by Ebastine.http://www.chictr.org.cn/showprojen.aspx?proj=49790(Accessed 1 May 2020) [Google Scholar] 
  1. Lau J.T., Leung P.C., Wong E.L., Fong C., Cheng K.F., Zhang S.C. The use of an herbal formula by hospital care workers during the severe acute respiratory syndrome epidemic in Hong Kong to prevent severe acute respiratory syndrome transmission, relieve influenza-related symptoms, and improve quality of life: a prospective cohort study. J. Altern. Complement. Med. 2005;11:49–55. doi: 10.1089/acm.2005.11.49. [PubMed] [CrossRef] [Google Scholar] 
  1. D’Andrea G. Quercetin: A flavonol with multifaceted therapeutic applications? Fitoterapia. 2015;106:256–271. doi: 10.1016/j.fitote.2015.09.018. [PubMed] [CrossRef] [Google Scholar] 
  1. Li Y., Yao J., Han C., Yang J., Chaudhry M.T., Wang S. Quercetin, inflammation and immunity. Nutrients. 2016;8:167. doi: 10.3390/nu8030167. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Wu W., Li R., Li X., He J., Jiang S., Liu S. Quercetin as an antiviral agent inhibits influenza a virus (IAV) entry. Viruses. 2015;8 doi: 10.3390/v8010006. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Rojas A., Del C.J., Clement S., Lemasson M., Garcia-Valdecasas M., Gil-Gomez A. Effect of quercetin on hepatitis C virus life cycle: from viral to host targets. Sci. Rep. 2016;6:31777. doi: 10.1038/srep31777. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Yao C., Xi C., Hu K., Gao W., Cai X., Qin J. Inhibition of enterovirus 71 replication and viral 3C protease by quercetin. Virol. J. 2018;15:116. doi: 10.1186/s12985-018-1023-6. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Nguyen T.T., Woo H.J., Kang H.K., Nguyen V.D., Kim Y.M., Kim D.W. Flavonoid-mediated inhibition of SARS coronavirus 3C-like protease expressed in Pichia pastoris. Biotechnol. Lett. 2012;34:831–838. doi: 10.1007/s10529-011-0845-8. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Ryu Y.B., Jeong H.J., Kim J.H., Kim Y.M., Park J.Y., Kim D. Biflavonoids from Torreya nucifera displaying SARS-CoV 3CL(pro) inhibition. Bioorg. Med. Chem. 2010;18:7940–7947. doi: 10.1016/j.bmc.2010.09.035. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Kishore V., Yarla N.S., Bishayee A., Putta S., Malla R., Neelapu N.R. Multi-targeting andrographolide and its natural analogs as potential therapeutic agents. Curr. Top. Med. Chem. 2017;17:845–857. doi: 10.2174/1568026616666160927150452. [PubMed] [CrossRef] [Google Scholar] 
  1. Gupta S., Mishra K.P., Ganju L. Broad-spectrum antiviral properties of andrographolide. Arch. Virol. 2017;162:611–623. doi: 10.1007/s00705-016-3166-3. [PubMed] [CrossRef] [Google Scholar] 
  1. Ding Y., Chen L., Wu W., Yang J., Yang Z., Liu S. Andrographolide inhibits influenza A virus-induced inflammation in a murine model through NF-kappaB and JAK-STAT signaling pathway. Microbes Infect. 2017;19:605–615. doi: 10.1016/j.micinf.2017.08.009. [PubMed] [CrossRef] [Google Scholar] 
  1. Uttekar M.M., Das T., Pawar R.S., Bhandari B., Menon V., Nutan Anti-HIV activity of semisynthetic derivatives of andrographolide and computational study of HIV-1 gp120 protein binding. Eur. J. Med. Chem. 2012;56:368–374. doi: 10.1016/j.ejmech.2012.07.030. [PubMed] [CrossRef] [Google Scholar] 
  1. Wintachai P., Kaur P., Lee R.C., Ramphan S., Kuadkitkan A., Wikan N. Activity of andrographolide against chikungunya virus infection. Sci. Rep. 2015;5:14179. doi: 10.1038/srep14179. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Panraksa P., Ramphan S., Khongwichit S., Smith D.R. Activity of andrographolide against dengue virus. Antiviral Res. 2017;139:69–78. doi: 10.1016/j.antiviral.2016.12.014. [PubMed] [CrossRef] [Google Scholar] 
  1. Paemanee A., Hitakarun A., Wintachai P., Roytrakul S., Smith D.R. A proteomic analysis of the anti-dengue virus activity of andrographolide. Biomed. Pharmacother. 2019;109:322–332. doi: 10.1016/j.biopha.2018.10.054. [PubMed] [CrossRef] [Google Scholar] 
  1. Wang D., Guo H., Chang J., Wang D., Liu B., Gao P. Andrographolide prevents EV-D68 replication by inhibiting the acidification of virus-containing endocytic vesicles. Front. Microbiol. 2018;9:2407. doi: 10.3389/fmicb.2018.02407. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Yu B., Dai C.Q., Jiang Z.Y., Li E.Q., Chen C., Wu X.L. Andrographolide as an anti-H1N1 drug and the mechanism related to retinoic acid-inducible gene-I-like receptors signaling pathway. Chin. J. Integr. Med. 2014;20:540–545. doi: 10.1007/s11655-014-1860-0. [PubMed] [CrossRef] [Google Scholar] 
  1. Enmozhi S.K., Raja K., Sebastine I., Joseph J. Andrographolide As a potential inhibitor of SARS-CoV-2 main protease: an in Silico Approach. J. Biomol. Struct. Dyn. 2020:1–10. doi: 10.1080/07391102.2020.1760136. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Farag M.A., Wessjohann L.A. Volatiles profiling in medicinal licorice roots using steam distillation and solid-phase microextraction (SPME) coupled to chemometrics. J. Food Sci. 2012;77:C1179–C1184. doi: 10.1111/j.1750-3841.2012.02927.x. [PubMed] [CrossRef] [Google Scholar] 
  1. Pilcher H. Liquorice may tackle SARS. Nature. 2003 doi: 10.1038/news030609-16. [CrossRef] [Google Scholar] 
  1. Cinatl J., Morgenstern B., Bauer G., Chandra P., Rabenau H., Doerr H.W. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet. 2003;361:2045–2046. doi: 10.1016/s0140-6736(03)13615-x. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Hoever G., Baltina L., Michaelis M., Kondratenko R., Baltina L., Tolstikov G.A. Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus. J. Med. Chem. 2005;48:1256–1259. doi: 10.1021/jm0493008. [PubMed] [CrossRef] [Google Scholar] 
  1. Utsunomiya T., Kobayashi M., Pollard R.B., Suzuki F. Glycyrrhizin, an active component of licorice roots, reduces morbidity and mortality of mice infected with lethal doses of influenza virus. Antimicrob. Agents Chemother. 1997;41:551–556. [PMC free article] [PubMed] [Google Scholar] 
  1. Chen H., Du Q. Potential natural compounds for preventing SARS-CoV-2 (2019-nCoV) infection. Preprints. 2020 doi: 10.20944/preprints202001.0358.v3. 2020010358. [CrossRef] [Google Scholar] 
  1. Lili H., Puyang G., Yue F., Wei Z., Enlong W., Jian G. Analysis on the application of Traditional Chinese Medicine in the treatment of COVID-19 by suppressing cytokine storm. Chinese Traditional and Herbal Drugs. 2020 [Google Scholar] 
  1. Chen H.S., Qi S.H., Shen J.G. One-Compound-Multi-Target: Combination Prospect of Natural Compounds with Thrombolytic Therapy in Acute Ischemic Stroke. Curr. Neuropharmacol. 2017;15:134–156. doi: 10.2174/1570159x14666160620102055. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Ishfaq M., Chen C., Bao J., Zhang W., Wu Z., Wang J. Baicalin ameliorates oxidative stress and apoptosis by restoring mitochondrial dynamics in the spleen of chickens via the opposite modulation of NF-kappaB and Nrf2/HO-1 signaling pathway during Mycoplasma gallisepticum infection. Poult. Sci. 2019;98:6296–6310. doi: 10.3382/ps/pez406. [PubMed] [CrossRef] [Google Scholar] 
  1. Chen F., Chan K.H., Jiang Y., Kao R.Y., Lu H.T., Fan K.W. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J. Clin. Virol. 2004;31:69–75. doi: 10.1016/j.jcv.2004.03.003. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Deng Y.F., Aluko R.E., Jin Q., Zhang Y., Yuan L.J. Inhibitory activities of baicalin against renin and angiotensin-converting enzyme. Pharm. Biol. 2012;50:401–406. doi: 10.3109/13880209.2011.608076. [PubMed] [CrossRef] [Google Scholar] 
  1. Hu G., Peng C., Xie X., Zhang S., Cao X. Availability, Pharmaceutics, Security, Pharmacokinetics, and Pharmacological Activities of Patchouli Alcohol. Evid. Complement. Alternat. Med. 2017;2017 doi: 10.1155/2017/4850612. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Kindrachuk J., Ork B., Hart B.J., Mazur S., Holbrook M.R., Frieman M.B. Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis. Antimicrob. Agents Chemother. 2015;59:1088–1099. doi: 10.1128/AAC.03659-14. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Yu Y., Zhang Y., Wang S., Liu W., Hao C., Wang W. Inhibition effects of patchouli alcohol against influenza a virus through targeting cellular PI3K/Akt and ERK/MAPK signaling pathways. Virol. J. 2019;16:163. doi: 10.1186/s12985-019-1266-x. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Li Y.C., Peng S.Z., Chen H.M., Zhang F.X., Xu P.P., Xie J.H. Oral administration of patchouli alcohol isolated from Pogostemonis Herba augments protection against influenza viral infection in mice. Int. Immunopharmacol. 2012;12:294–301. doi: 10.1016/j.intimp.2011.12.007. [PubMed] [CrossRef] [Google Scholar] 
  1. Manzoor M.F., Ahmad N., Ahmed Z., Siddique R., Zeng X.A., Rahaman A. Novel extraction techniques and pharmaceutical activities of luteolin and its derivatives. J. Food Biochem. 2019;43 doi: 10.1111/jfbc.12974. [PubMed] [CrossRef] [Google Scholar] 
  1. Yan H., Ma L., Wang H., Wu S., Huang H., Gu Z. Luteolin decreases the yield of influenza A virus in vitro by interfering with the coat protein I complex expression. J. Nat. Med. 2019;73:487–496. doi: 10.1007/s11418-019-01287-7. [PubMed] [CrossRef] [Google Scholar] 
  1. Peng M., Swarbrick C., Chan K.W., Luo D., Zhang W., Lai X. Luteolin escape mutants of dengue virus map to prM and NS2B and reveal viral plasticity during maturation. Antiviral Res. 2018;154:87–96. doi: 10.1016/j.antiviral.2018.04.013. [PubMed] [CrossRef] [Google Scholar] 
  1. Tsai Y.C., Hohmann J., El-Shazly M., Chang L.K., Danko B., Kusz N. Bioactive constituents of Lindernia crustacea and its anti-EBV effect via Rta expression inhibition in the viral lytic cycle. J. Ethnopharmacol. 2020;250 doi: 10.1016/j.jep.2019.112493. [PubMed] [CrossRef] [Google Scholar] 
  1. Li B.Q., Fu T., Dongyan Y., Mikovits J.A., Ruscetti F.W., Wang J.M. Flavonoid baicalin inhibits HIV-1 infection at the level of viral entry. Biochem. Biophys. Res. Commun. 2000;276:534–538. doi: 10.1006/bbrc.2000.3485. [PubMed] [CrossRef] [Google Scholar] 
  1. Lin C.W., Tsai F.J., Tsai C.H., Lai C.C., Wan L., Ho T.Y. Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds. Antiviral Res. 2005;68:36–42. doi: 10.1016/j.antiviral.2005.07.002. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Joshi R.S., Jagdale S.S., Bansode S.B., Shankar S.S., Tellis M.B., Pandya V.K. Discovery of potential multi-target-Directed ligands by targeting host-specific SARS-CoV-2 structurally conserved main protease($) J. Biomol. Struct. Dyn. 2020:1–16. doi: 10.1080/07391102.2020.1760137. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Ho T.Y., Wu S.L., Chen J.C., Li C.C., Hsiang C.Y. Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction. Antiviral Res. 2007;74:92–101. doi: 10.1016/j.antiviral.2006.04.014. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Schwarz S., Wang K., Yu W., Sun B., Schwarz W. Emodin inhibits current through SARS-associated coronavirus 3a protein. Antiviral Res. 2011;90:64–69. doi: 10.1016/j.antiviral.2011.02.008. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Lin S.C., Ho C.T., Chuo W.H., Li S., Wang T.T., Lin C.C. Effective inhibition of MERS-CoV infection by resveratrol. BMC Infect. Dis. 2017;17:144. doi: 10.1186/s12879-017-2253-8. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Schwarz S., Sauter D., Wang K., Zhang R., Sun B., Karioti A. Kaempferol derivatives as antiviral drugs against the 3a channel protein of coronavirus. Planta Med. 2014;80:177–182. doi: 10.1055/s-0033-1360277. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Wen C.C., Kuo Y.H., Jan J.T., Liang P.H., Wang S.Y., Liu H.G. Specific plant terpenoids and lignoids possess potent antiviral activities against severe acute respiratory syndrome coronavirus. J. Med. Chem. 2007;50:4087–4095. doi: 10.1021/jm070295s. [PubMed] [CrossRef] [Google Scholar] 
  1. Park J.Y., Kim J.H., Kim Y.M., Jeong H.J., Kim D.W., Park K.H. Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases. Bioorg. Med. Chem. 2012;20:5928–5935. doi: 10.1016/j.bmc.2012.07.038. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. Jin Z., Du X., Xu Y., Deng Y., Liu M., Zhao Y. Structure-based drug design, virtual screening and high-throughput screening rapidly identify antiviral leads targeting COVID-19. bioRxiv. 2020 doi: 10.1101/2020.02.26.964882. 2020.02.26.964882. [CrossRef] [Google Scholar] 
  1. Yang M., Chen F., Zhu D., Li J., Zhu J., Zeng W. Clinical efficacy of Matrine and Sodium Chloride Injection in treatment of 40 cases of COVID-19. China J. Chinese Matera Med. 2020:1–12. [PubMed] [Google Scholar]
  1. 2020. News.http://www.jksb.com.cn/html/2020/pingce_0320/161235.html(Accessed 29 April 2020) [Google Scholar] 
  1. Wang R., Yang S., Xie C., Shen Q., Li M., Lei X. Clinical observation of qingfeipaidu decoction in the treatment of novel coronavirus pneumonia. Pharmacol. Clin. Chin. Mater. Med. 2020:1–14. [Google Scholar] 
  1. Runfeng L., Yunlong H., Jicheng H., Weiqi P., Qinhai M., Yongxia S. Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2) Pharmacol. Res. 2020;156 doi: 10.1016/j.phrs.2020.104761. [PMC free article] [PubMed] [CrossRef] [Google Scholar] 
  1. 2020. News.http://www.xinhuanet.com/politics/2020-02/12/c_1125561735.htm(Accessed 29 April 2020) [Google Scholar] 
  1. Cui H., Li Y., Guo L., Liu X., Wang L., Jia J. Traditional Chinese medicine for treatment of coronavirus disease 2019: a review. Tradit. Med. Res. 2020;5:65–73. doi: 10.12032/TMR20200222165. [CrossRef] [Google Scholar] 
  1. Chan K.W., Wong V.T., Tang S. COVID-19: An Update on the Epidemiological, Clinical, Preventive and Therapeutic Evidence and Guidelines of Integrative Chinese-Western Medicine for the Management of 2019 Novel Coronavirus Disease. Am. J. Chin. Med. 2020:1–26. doi: 10.1142/S0192415X20500378. [PubMed] [CrossRef] [Google Scholar] 
  1. Ohashi H., Watashi K., Saso W., Shionoya K., Iwanami S., Hirokawa T. Multidrug treatment with nelfinavir and cepharanthine against COVID-19. bioRxiv. 2020 doi: 10.1101/2020.04.14.039925. 2020.04.14.039925. [CrossRef] [Google Scholar]
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