key: cord-0910278-gb6eie41 authors: Xian, Yanfang; Zhang, Juan; Bian, Zhaoxiang; Zhou, Hua; Zhang, Zhenbiao; Lin, Zhixiu; Xu, Hongxi title: Bioactive natural compounds against human coronaviruses: a review and perspective date: 2020-06-08 journal: Acta Pharm Sin B DOI: 10.1016/j.apsb.2020.06.002 sha: 181b6dd7d6431d68e707774e40155f60a42049ed doc_id: 910278 cord_uid: gb6eie41 Coronaviruses (CoVs), a family of enveloped positive-sense RNA viruses, are characterized by club-like spikes that project from their surface, unusually large RNA genome, and unique replication capability. CoVs are known to cause various potentially lethal human respiratory infectious diseases, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and the very recent coronavirus disease 2019 (COVID-19) outbreak. Unfortunately, neither drug nor vaccine has yet been approved to date to prevent and treat these diseases caused by CoVs. Therefore, effective prevention and treatment medications against human coronavirus are in urgent need. In the past decades, many natural compounds have been reported to possess multiple biological activities, including antiviral properties. In this article, we provided a comprehensive review on the natural compounds that interfere with the life cycles of SARS and MERS, and discussed their potential use for the treatment of COVID-19. Chinese herbal medicines and natural compounds possess promising antiviral effects against Human coronaviruses (HCoVs) and provide a rich resource for novel antiviral drug development. This review provides an update on natural compounds against HCoVs and summarizes the active natural compounds and their possible action mechanisms. Coronaviruses (CoVs) comprise a large family of RNA viruses that infect a wide variety of mammalian and avian hosts, and cause a broad spectrum of diseases 1 . CoVs have a single-stranded, positive-sense RNA genome and comprise four genera of α-, β-, γand δ-coronaviruses 2, 3 . CoVs are prone to mutation and recombination during replication, and this propensity has contributed to the diversity of coronavirus. Human coronaviruses (HCoVs) are known respiratory pathogens associated with a wide range of respiratory outcomes 4 . The advent of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) in the past two decades have thrust HCoVs into the spotlight in the research community due to their high pathogenicity in humans 5 . More recently, the sudden emergence of a new coronavirus discovered at the end of 2019 has caused a major outbreak of human fatal pneumonia with a widespread global impact, and this infectious disease caused by the new coronavirus has been named coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO) 6, 7 . We have now known that the causative agent of this outbreak is a novel coronavirus phylogenetically in the SARS-CoV clade, hence referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 is more widespread than the SARS-CoV 8, 9 . The common respiratory symptoms of a person infected with coronavirus include fever, cough, shortness of breath, and dyspnea. In more severe cases, infection can cause pneumonia, severe acute respiratory syndrome, kidney failure and even death 10, 11 . By 20 May 2020, this potentially fatal virus has caused more than 4.98 million confirmed infected cases and resulted in over 327,000 deaths globally. COVID-19 has spread to more than 200 countries around the world, and its outbreak has seen no signs of abating. Unfortunately, despite extensive efforts have been devoted to the development of anti-coronavirus agents, effective therapeutics for coronavirus infection have remained elusive so far 12 . A lack of effective immunization and antiviral drugs poses a daunting challenge to current global efforts to contain the COVID-19 outbreak 13, 14 . Thus, there clearly exists an unmet medical need for effective antivirals to manage the current COVID-19 pandemic. Herbal medicines and medicinal plant-based natural compounds provide a rich resource for novel antiviral drug development. Some 29, 30 . To date, dozens of Chinese herbs and hundreds of natural compounds have been reported to possess antiviral activities. The past few decades have also witnessed tremendous efforts in revealing the antiviral action mechanisms of these natural agents on the influence of the viral life cycle, such as viral entry, replication, assembly, and release, as well as virus-host-specific interactions. The purpose of this review is to provide an update on natural products that have promising antiviral effects against coronaviruses and discuss their molecular targets and mechanisms. To understand the life cycle and pathogenesis of coronavirus is of importance for the development of anti-CoV agents. Coronavirus infection is initiated by the binding of virions to cellular receptors ( Fig. 1) . This sets off a series of events culminating in the deposition of the nucleocapsid into the cytoplasm, where the viral genome becomes available for translation. Insert Fig. 1 The route of the SARS-CoV entry into humans is through the respiratory tract mainly by droplet transmission. The surface envelops spike protein (S protein) of SARS-CoV-2 plays an important role in establishing infection and determining the cell and tissue tropism 31 . The initial attachment of the virion to the host cell is initiated by interactions between the S protein and its receptor 32 . Entry of the virus requires receptor binding, followed by conformational change of the S protein, and then cathepsin L-mediated proteolysis within the endosome. The angiotensin-converting enzyme 2 (ACE2), found in the lower respiratory tract of humans, is known as cell host receptor for SARS-CoV, and is expressed in a wide variety of body tissues and regulates both cross-species and human-to-human transmission 33 . Through analyzing the bronchoalveolar lavage fluid (BALF) from a COVID-19 patient, Zhou et al. 34 and Walls et al. 35 have confirmed that SARS-CoV-2 uses the same cellular entry receptor, ACE2, as does the SARS-CoV. The virion S glycoprotein on the surface of the coronavirus can attach to the ACE2 receptor on the surface of human cells 34 . Following receptor binding, the virus must next gain access to the host cell cytosol, and this is generally accomplished by acid-dependent proteolytic cleavage of S protein by a cathepsin or another protease, followed by fusion of the viral and cellular membranes. S glycoprotein includes two subunits, S1 and S2 32 . S1 determines the virus-host range and cellular tropism with the key function domain (RBD), while S2 mediates virus-cell membrane fusion by two tandem domains, heptad repeats 1 (HR1) and HR2 36 Nucleocapsids are formed from the encapsidation of progeny genomes by N protein, and these coalesce with the membrane-bound components, forming virions by budding into the ERGIC 11, 38 . Lastly, the virion-containing vesicles fuse with the plasma membrane to release the virus. Extensive studies have been conducted over the past years to identify anti-CoV agents from natural products and Chinese herbal medicine 39 . In this section, we discuss the medicinal plant-based natural compounds and traditional Chinese medicine (TCM) formulae with antiviral action against coronaviruses and their potential for use in clinical practice. Various natural products have shown potent antiviral effects against SARS-CoV 40-43 ， MERS-CoV 44 , HCoV-229E 45 and HCoV-OC43 46 . Aescin isolated from Aesculus hippocastanum and reserpine isolated from various Rauwolfia species 40 Table 1 29, 30, [41] [42] [43] [44] [45] [46] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] , while their chemical structures shown in Fig. 2 . This article also reported the IC 50 values of the natural products against the HCoVs including SARS and MERS. As shown in Table 1 , the IC 50 values of these compounds mostly ranged from micro to milligrams per milliliter, or from nano to micromoles per liter. These natural compounds have been reported to act on various viral targets such as spike (S) glycoprotein, coronavirus main proteinase-chymotrypsin-like protease (3CLpro), the papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), and nucleocapsid (N) proteins. These pharmacological targets are further discussed in the section below. Insert Table 1 and Fig. 2 Table 2 [58] [59] [60] 62, [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] Herba have been found to exert antimicrobial activities. Insert Table 2 4 Natural products alone and TCM herbal formulae have antiviral activities against coronaviruses through acting on different molecular targets. We summarized the molecular targets of natural products against coronavirus, and these targets include S glycoprotein, coronavirus main 3CLpro, PLpro, RdRp, N proteins and other kinase such as viral helicase. The coronavirus spike (S) glycoprotein is the main antigen presented at the viral surface and is the target of neutralizing antibodies during infection, and a focus of vaccine design. S is a class I viral fusion protein synthesized as a single polypeptide chain precursor of approximately 1300 amino acids. For many coronaviruses, S is processed by host proteases to generate two subunits, designated S1 and S2, which remain non-covalently bound in the pre-fusion conformation 82 3CLpro is an essential part of the polyprotein and is usually present as a monomer. However, upon substrate binding, dimer formation has been observed. Each monomer has two domains (I and II) along with a C-terminal domain. 3CLpro is an important drug target, as its protease activity is crucial for viral survival and replication 86 . PLpro enzyme has two distinct functions in viral pathogenesis. The first one is to process the viral polyprotein into individual proteins that are essential for viral replication. The second is to remove ubiquitin and ISG15 proteins from host cell proteins, which likely helps coronaviruses shun the host's innate immune response 87 RdRp, also called RNA replicases, is an important protease that catalyzes the The N protein is the only structural protein that is associated with RTCs. It binds to the gRNA, and is essential for the incorporation of the virus genetic material into CoV particles. Moreover, it is the major component of ribonucleoprotein complex sitting in the virion cores, and thus also plays an essential architectural role in the virus particle structural organization through a network of interactions with the gRNA, M protein and other N molecules. For CoVs, N protein primarily encapsidates the viral genome but also plays an important role in viral replication, virus particle assembly and release 93, 94 . Due to its pivotal role in the incorporation of the virus genetic material into CoV particles, it has been recognized as an important target for various antiviral compounds. Resveratrol, a well-known natural compound widely presented in different plants, including Vitis vinifera, Polygonum cuspidatum and Vaccinium macrocarpon, has been demonstrated to decrease the production of nitric oxide in tissue to reduce inflammation 95, 96 . It also acts as an antioxidant to remove free radicals to suppress tumor growth 97 and treat age-related diseases 98, 99 . Moreover, resveratrol has been shown to have antiviral activity on MERS-CoV via targeting N protein and prolong cellular survival after viral infection 30 . Besides targeting S protein, 3CLpro, PLpro, RdRp, and N proteins, natural products can also target on other proteins to exert their anti-CoV activities. Glycyrrhizin, an active ingredient of Glycyrrhizae Radix et Rhizoma, has been observed to exert anti-SARS-CoV activity through targeting protein kinase C, which upregulates the nitrous synthase and production 29, 49 . Viral helicase is essential for subsequent viral replication and proliferation, and is considered as a potential target for antiviral therapy 100 . Natural compounds such as myricetin and scutellarein, potently inhibited the SARS-CoV helicase protein by affecting the ATPase activity 56 . As shown in Fig. 3 , CoV relies on its spike proteins to bind to the host cell surface receptor for entry. For SARS-CoV-2, it is now known that this receptor is ACE2 101 . After the virus entries into the host cell, its positive genomic RNA attaches directly to the host ribosome for the translation of two large, coterminal polyproteins that are processed by proteolysis into components for packaging new virions. Two proteases that participate in this proteolysis process are 3CLpro and PLpro. In order to replicate the RNA genome, the CoV encodes a replicase that is a RdRp. These four proteins are essential for the pathogenicity of virus. Therapeutics currently targeting spike, RdRp, 3CLpro, and PLpro are possible treatments for SARS-CoV-2 102 . Moreover, the initial analyses of genomic sequences from COVID-19 patients indicate that the catalytic sites of the four COVID-19 enzymes that could represent antiviral targets are highly conserved and share a high level of sequence similarity with the corresponding SARS and MERS enzymes. SARS-CoV-2 shares 82% similarity of sequence identity with SARS-CoV and more than 90% similarity of sequence identity in several essential enzymes 103 . Therefore, it is rational to consider repurposing existing MERS and SARS inhibitors for COVID-19 treatment 102 . As listed in Table 1 The authors declare that they have no competing interests. Human coronaviruses: a review of virus-host interactions Coronaviruses-drug discovery and therapeutic options Structure, function, and evolution of coronavirus Spike proteins Coronavirus envelope protein: current knowledge From SARS to MERS, thrusting coronaviruses into the spotlight Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods Phase-adjusted estimation of the number of coronavirus disease 2019 cases in Wuhan Coronaviridae study group of the international committee on taxonomy of V. The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2 The reproductive number of COVID-19 is higher compared to SARS coronavirus Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak-an update on the status Reversal of the progression of fatal coronavirus infection in cats by a broad-spectrum coronavirus protease inhibitor The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from middle east respiratory syndrome coronavirus Antiviral natural products and herbal medicines Antiviral traditional medicines against herpes-simplex virus (Hsv-1), poliovirus, and measles-virus in-vitro and their therapeutic efficacies for Hsv-1 infection in mice Hepatitis C virus and natural compounds: a new antiviral approach Antiviral flavonoids from the root bark of Morus alba L Isolation and characterization of an anti-HSV polysaccharide from Prunella vulgaris A new hydrolyzable tannin from geum-japonicum and its antiviral activity Isolation and structure of woodorien, a new glucoside having antiviral activity, from woodwardia orientalis Antiviral potential of natural compounds against influenza virus hemagglutinin The cranberry extract oximacro® exerts in vitro virucidal activity against influenza virus by interfering with hemagglutinin Anti-HIV triterpene acids from Geum japonicum A new anti-HIV triterpene from Geum japonicum Screening of traditional medicines for their inhibitory activity against HIV-1 protease Juncus maritimus, is a new inhibitor of hepatitis C virus RNA replication Matrine-type alkaloids from the roots of sophora flavescens and their antiviral activities against the hepatitis B virus Harzianoic acids A and B, new natural scaffolds with inhibitory effects against hepatitis C virus Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus Effective inhibition of MERS-CoV infection by resveratrol Severe acute respiratory syndrome vs. the middle east respiratory syndrome Coronaviruses: an overview of their replication and pathogenesis Receptor recognition by the novel coronavirus from wuhan: an analysis based on decade-long structural studies of SARS coronavirus A pneumonia outbreak associated with a new coronavirus of probable bat origin Structure, function, and antigenicity of the SARS-CoV-2 Spike glycoprotein Measures for diagnosing and treating infections by a novel coronavirus responsible for a pneumonia outbreak originating in Wuhan Coronavirus transcription: a perspective The molecular biology of coronaviruses Targeting apoptosis pathways in cancer by Chinese medicine Reserpine: a challenge for total synthesis of natural products Small molecules targeting severe acute respiratory syndrome human coronavirus Bioactive coumarins from Boenninghausenia sessilicarpa Identification of natural compounds with antiviral activities against SARS-associated coronavirus Safe, high-throughput screening of natural compounds of MERS-CoV entry inhibitors using a pseudovirus expressing MERS-CoV spike protein Antiviral effects of saikosaponins on human coronavirus 229E in vitro Natural bis-benzylisoquinoline alkaloids-tetrandrine, fangchinoline, and cepharanthine, inhibit human coronavirus OC43 infection of MRC-5 human lung cells Ginsenoside Rb1: the anti-ulcer constituent from the head of Panax ginseng Repurposing of clinically approved drugs for treatment of coronavirus disease 2019 in a 2019-novel coronavirus-related coronavirus model Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction SARS-CoV 3CLpro inhibitory effects of quinone-methide triterpenes from Tripterygium regelii Binding interaction of quercetin-3-beta-galactoside and its synthetic derivatives with SARS-CoV 3CL(pro): structure−activity relationship studies reveal salient pharmacophore features Tanshinones as selective and slow-binding inhibitors for SARS-CoV cysteine proteases Diarylheptanoids from Alnus japonica inhibit papain-like protease of severe acute respiratory syndrome coronavirus The potential chemical structure of anti-SARS-CoV-2 RNA-dependent RNA polymerase Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13 Chalcones isolated from Angelica keiskei inhibit cysteine proteases of SARS-CoV The Chinese prescription lianhuaqingwen capsule exerts anti-influenza activity through the inhibition of viral propagation and impacts immune function Effect of lianhuaqingwen capsules on airway inflammation in patients with acute exacerbation of chronic obstructive pulmonary disease Qualitative and quantitative analysis of the major constituents in Chinese medical preparation Lianhua-Qingwen capsule by UPLC-DAD-QTOF-MS Inhibitory effects of three precriptions of traditional chinese medicine on SARS-associated coronavirus in vitro COVID-19 suspected cases treated with Lianhua Qingwen decoction: a clinical observation of 63 cases Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2) Efficacy and safety of Lianhuaqingwen capsules, a repurposed Chinese herb, in patients with Coronavirus disease 2019: a multicenter, prospective, randomized controlled trial Retrospective clinical analysis on treatment of novel coronavirus-infected pneumonia with traditional chinese medicine Lianhua Qingwen National Medical Products Administration of the People's Republic of China The network pharmacology for treatment of COVID-19 with Renshenbaidusan based on cytokines. Chin Tradit Herbal Drugs 2020 In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds National Health Commission of the People's Republic of China. Notice on the issunance of guidelines of diagnosis and treatment for 2019-nCoV infected pneumonia Treating influenza patients of wind-heat affecting Fei syndrome by jinhua qinggan granule: a double-blinded randomized control trial Complementary and alternative medicine is expected to make greater contribution in controlling the prevalence of influenza Shufeng Jiedu Capsule protect against acute lung injury by suppressing the MAPK/NF-kappaB pathway Shufeng Jiedu capsules alleviate lipopolysaccharide-induced acute lung inflammatory injury via activation of GPR18 by verbenalin A module analysis approach to investigate molecular mechanism of TCM formula: a trial on Shu-feng-jie-du formula Xuebijing injection in the treatment of severe pneumonia: study protocol for a randomized controlled trial Xing Shi Gan decoction attenuates PM2.5 induced lung injury via inhibiting HMGB1/TLR4/NFkappaB signal pathway in rat Experiment study on Ma-Xing-Shi-Gan-Tang (MXSGT) and its decomposed recipes on anti-influenza virus A in vitro Chinese medicine injection shuanghuanglian for treatment of acute upper respiratory tract infection: a systematic review of randomized controlled trials Antiviral effects of Shuanghuanglian injection powder against influenza A virus H5N1 in vitro and in vivo Effects of different principles of traditional chinese medicine treatment on TLR7/NF-kappaB signaling pathway in influenza virus infected mice The effects and mechanism of Yinqiao Powder on upper respiratory tract infection Structural basis for human coronavirus attachment to sialic acid receptors Coronavirus spike protein and tropism changes Tectonic conformational changes of a coronavirus spike glycoprotein promote membrane fusion Emodin inhibits current through SARS-associated coronavirus 3a protein Middle East respiratory syndrome coronavirus: transmission, virology and therapeutic targeting to aid in outbreak control Structural basis for the ubiquitin-linkage specificity and deISGylating activity of SARS-CoV papain-like protease Deubiquitination, a new function of the severe acute respiratory syndrome coronavirus papain-like protease? The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds RNA-dependent RNA polymerases and their emerging roles in antiviral therapy Immunomodulatory and anti-SARS activities of Houttuynia cordata Coronavirus nucleocapsid proteins assemble constitutively in high molecular oligomers Overexpression of the nucleocapsid protein of Middle East respiratory syndrome coronavirus up-regulates CXCL10 Resveratrol attenuates inflammatory hyperalgesia by inhibiting glial activation in mice spinal cords Resveratrol decreases nitric oxide production by hepatocytes during inflammation Resveratrol: a potential challenger against gastric cancer Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and downregulation of NADPH oxidase Effects of exercise training and resveratrol on vascular health in aging A high ATP concentration enhances the cooperative translocation of the SARS coronavirus helicase nsP13 in the unwinding of duplex Genomic and protein structure modelling analysis depicts the origin and pathogenicity of 2019-nCoV Learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-nCoV Therapeutic options for the 2019 novel coronavirus (2019-nCoV) A new coronavirus associated with human respiratory disease in China A genomic perspective on the origin and emergence of SARS-CoV-2 A role for CT in COVID-19? What data really tell us so far COVID-19 cacophony: is there any orchestra conductor? COVID-19: consider cytokine storm syndromes and immunosuppression Pulmonary involvement in patients with hemophagocytic lymphohistiocytosis Traditional chinese medicine in the treatment of acute respiratory tract infections Emodin alleviates alternatively activated macrophage and asthmatic airway inflammation in a murine asthma model Emodin suppresses LPS-induced inflammation in RAW264.7 cells through a PPAR gamma-dependent pathway Emodin induces apoptosis in human promyeloleukemic HL-60 cells accompanied by activation of caspase 3 cascade but independent of reactive oxygen species production Effect of Siam weed extract and its bioactive component scutellarein tetramethyl ether on anti-inflammatory activity through NF-kappa B pathway Glycyrrhizin ameliorates inflammatory pain by inhibiting microglial activation-mediated inflammatory response via blockage of the HMGB1-TLR4-NF-kB pathway Flos lonicerae flavonoids attenuate experimental ulcerative colitis in rats via suppression of NF-kappaB signaling pathway Resveratrol attenuates allergic asthma and associated inflammation in the lungs through regulation of miRNA-34a that targets FoxP3 in mice The microbial metabolite desaminotyrosine protects from influenza through type I interferon On the use of corticosteroids for 2019-nCoV pneumonia The immunopharmaceutical effects and mechanisms of herb medicine Efficacy and safety of integrated traditional Chinese and Western medicine for corona virus disease 2019 (COVID-19): a systematic review and meta-analysis Effect of integrated traditional Chinese and Western medicine on SARS: a review of clinical evidence Improving solubility and chemical stability of natural compounds for medicinal use by incorporation into liposomes Dry antibiotic pipeline: regulatory bottlenecks and regulatory reforms -IC 50 value or the mechanism of antiviral activity of these active compounds is not clear.