key: cord-0692888-e3gok0ot authors: Huang, Fangfang; Li, Ying; Leung, Elaine Lai-Han; Liu, Xiaohua; Liu, Kaifeng; Wang, Qu; Lan, Yongqi; Li, Xiaoling; Yu, Haibing; Cu, Liao; Luo, Hui; Luo, Lianxiang title: A review of therapeutic agents and Chinese herbal medicines against SARS-COV-2 (COVID-19) date: 2020-05-20 journal: Pharmacol Res DOI: 10.1016/j.phrs.2020.104929 sha: 42c46e8ef64dfa8d30788c8ca6e06238d4d916a8 doc_id: 692888 cord_uid: e3gok0ot 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. broad-spectrum antiviral drug in the prevention and treatment of malaria [34] . CQ/HCQ block viral from entering into cells by inhibiting glycosylation of host receptors, proteolytic processing, and endosomal acidification, as well as regulate immunity through attenuation of cytokine production, inhibition of autophagy and lysosomal activity in host cells [35, 36] . CQ can inhibit SARS-CoV-2 infection at a low-micro molar concentration and HCQ is more potent than CQ [37, 38] . A multicenter clinical trial involving more than a dozen hospitals in China showed that CQ can improve radiologic findings, enhance viral clearance and reduce disease progression in the treatment of patients with COVID-19, so China has included CQ in the recommendations regarding the prevention and treatment of COVID-19 [37, 39, 40] . At the same time, another clinical trial showed that HCQ can significantly shorten the clinical recovery time and promote the absorption of pneumonia among patients with COVID-19 [41] . Notably, azithromycin reinforced the effect of CQ/HCQ in COVID-19 patients, but the publishing journal's society subsequently declared that the trial did "not meet the Society's expected Standard" [42, 43] . Conversely, the higher CQ dosage should not be recommended for critically ill patients with COVID-19 because of its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir [44, 45] . In summary, although CQ/HCQ have shown anti-SARS-CoV-2 efficacy both in vivo and in vitro trials as well as relatively well tolerated, some clinical trial designs and outcome data have not been submitted or published to peer review [46] . It is not recommended in the use of CQ/HCQ for COVID-19 outside of the hospital or a clinical trial due to lack of reliable efficacy data and potential toxic effects [47, 48] . Remdesivir (GS-5734), a prodrug of GS-441524 developed by the American pharmaceutical company Gilead Sciences, showed promise at the peak of the Ebola virus outbreak due to its low EC50 and host polymerase selectivity against the Ebola virus [49, 50] . Subsequently, research about it also showed significant anti-SARS-CoV and MERS-CoV activity [51, 52] . As a nucleoside analog with exonuclease resistance, remdesivir is metabolized to active nucleoside triphosphates that effectively prevents the elongation of the RNA chain by inhibiting RNA polymerase, but will not be digested with a viral exonuclease (nsp14) with proofreading activity [53] . Compared with ribavirin, penciclovir, nitazoxanide, nafamostat, chloroquine and favipiravir (T-705), remdesivir J o u r n a l P r e -p r o o f has the best efficacy and the lowest toxic side effects on anti-SARS-CoV-2 in Vero E6 cells [32] . The United States first reported the clinical case of remdesivir in the treatment of SARS-CoV-2 associated pneumonia [54] . Currently, a number of clinical trials are ongoing, aiming to verify the safety and antiviral activity of remdesivir in the treatment of COVID-19. Clinical findings of the team of Professor Cao Bin of the China-Japan Friendship Hospital suggested that the remdesivir is adequately tolerated but do not provide significant clinical or antiviral effects in severe patients with COVID-19 [55] . However, the results of the global clinical trial are believed that remdesivir can relieve symptoms and reduce mortality, especially for patients in intensive care who require mechanical ventilation [56] . Meanwhile, the clinical trials in Chicago have suggested that early COVID-19 patients benefit more due to the reduction of lung damage [57] . In conclusion, remdesivir is still in the consideration of one of the most promising drugs for treatment COVID-19 currently [58] . Lopinavir/Ritonavir (LPV/r), also known as Kaletra, is an oral combination agent for treating HIV approved by the FDA, which has shown anti-coronavirus efficacy in studies of SARS and MERS [59] [60] [61] [62] . As a new protease inhibitor, LPV/r interrupts viral nucleic acid replication via inhibition of 3CLpro [63] . Xushun Guo's team at Sun Yat-sen University School of Medicine derived a homology modeling to confirm that LPV/r significantly inhibited the function of CEP_C30 to prevent the SARS-CoV-2 reproduction cycle [64] . In addition, two groups in China and Korea have reported LPV/r can improve the clinical symptoms of patients with COVID-19 [65, 66] . Besides, LPV/r can achieve better antiviral effects when used with interferon or ninavir than alone [67] . However, the latest evidence suggests that it may cause liver damage and prolong hospital stay in the COVID-19 infected patients [68] . Furthermore, no benefit was observed with LPV/r treatment beyond standard care in hospitalized adult patients with severe COVID-19 [69] . Therefore, whether LPV/r can become an important adjuvant drug in anti-SARS-CoV-2 therapy and improve the clinical outcome of patients remains to be determined. J o u r n a l P r e -p r o o f 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 Figure 2 . 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. 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 J o u r n a l P r e -p r o o f 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. Glycyrrhizic acid is a plant product isolated from the traditional Chinese medicine licorice 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. Baicalin 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. 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. 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 J o u r n a l P r e -p r o o f 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. 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 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. All authors have read and approved the final submission. There is no conflict of interest associated with this article. 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