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冠状病毒(coronavirus,CoVs),在电子显微镜下呈“冠状”或冠状形态,因而命名为冠状病毒,可感染人类并容易引起急/慢性呼吸道系统疾病[1]。冠状病毒科分为α、β、γ和δ 4个属[2],已知感染人的冠状病毒共有7种,分别是HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU1、SARS-CoV,MERS-CoV和SARS-CoV-2,其中,前4种病毒致病性较低,一般仅引起类似普通感冒的轻度感染,后3种对人类健康产生严重威胁,具有较高的致死率,分别是2003年出现的冠状病毒(severe acute respiratory syndrome coronavirus,SARS-CoV)感染的严重急性呼吸道综合征、2012年在中东地区出现高致病性冠状病毒(Middle East respiratory syndrome coronavirus,MERS-CoV)感染的中东呼吸综合征和2019年出现的一种新型冠状病毒(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)感染引起的肺炎(Corona Virus Disease 2019,COVID-19)[3]。
Research progress on small molecule inhibitors of coronaviruses
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摘要: 冠状病毒感染严重威胁着人类健康,目前尚无特异性治疗药物或疫苗。近年来,针对SARS-CoV、MERS-CoV、SARS-CoV-2这3种高致病性冠状病毒的配体S蛋白、RdRp、PLpro和3CLpro等靶点,国内外研究者已经开发了多种小分子抑制剂。综述这些冠状病毒的特点、作用靶点、小分子抑制剂及其构效关系。
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关键词:
- 冠状病毒 /
- 严重急性呼吸系统综合征冠状病毒 /
- 中东呼吸综合征冠状病毒 /
- 新型冠状病毒 /
- 靶点 /
- 抑制剂
Abstract: Coronavirus infection seriously threatens human health. There is no specific medication or vaccine so far. In recent years, domestic and foreign researchers have developed a variety of small-molecule inhibitors against the ligand S protein, RdRp, PLpro and 3CLpro of three highly pathogenic coronavirus, SARS-CoV, MERS-CoV, SARS-CoV-2. This article reviews the characteristics of these coronaviruses, action targets, small molecule inhibitors, and structure-activity relationships.-
Key words:
- coronavirus /
- SARS-CoV /
- MERS-CoV /
- SARS-CoV-2 /
- targets /
- inhibitors
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[1] PERLMAN S, NETLAND J. Coronaviruses post-SARS: update on replication and pathogenesis[J]. Nat Rev Microbiol,2009,7(6):439-450. doi: 10.1038/nrmicro2147 [2] 刘昌孝, 王玉丽, 闫凤英. 认识新型冠状病毒肺炎, 关注疫情防控药物研发[J]. 中国抗生素杂志, 2020, 45(2):93-102. doi: 10.3969/j.issn.1001-8689.2020.02.001 [3] HUANG C L, WANG Y M, LI X W, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China[J]. Lancet,2020,395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5 [4] CUI J, LI F, SHI Z L. Origin and evolution of pathogenic coronaviruses[J]. Nat Rev Microbiol,2019,17(3):181-192. doi: 10.1038/s41579-018-0118-9 [5] 刘昌孝, 伊秀林, 王玉丽, 等. 认识新冠病毒(SARS-CoV-2), 探讨抗病毒药物研发策略[J]. 药物评价研究, 2020, 43(3):361-371. [6] GORBALENYA A E, SNIJDER E J, SPAAN W J. Severe acute respiratory syndrome coronavirus phylogeny: toward consensus[J]. J Virol,2004,78(15):7863-7866. doi: 10.1128/JVI.78.15.7863-7866.2004 [7] ZIEBUHR J, THIEL V, GORBALENYA A E. The autocatalytic release of a putative RNA virus transcription factor from its polyprotein precursor involves two paralogous papain-like proteases that cleave the same peptide bond[J]. J Biol Chem,2001,276(35):33220-33232. doi: 10.1074/jbc.M104097200 [8] ZUMLA A, CHAN J F W, AZHAR E I, et al. Coronaviruses: drug discovery and therapeutic options[J]. Nat Rev Drug Discov,2016,15(5):327-347. doi: 10.1038/nrd.2015.37 [9] DU L Y, HE Y X, ZHOU Y S, et al. The spike protein of SARS-CoV: a target for vaccine and therapeutic development[J]. Nat Rev Microbiol,2009,7(3):226-236. doi: 10.1038/nrmicro2090 [10] PILLAIYAR T, MANICKAM M, NAMASIVAYAM V, et al. An overview of severe acute respiratory syndrome-coronavirus (SARS-CoV) 3CL protease inhibitors: peptidomimetics and small molecule chemotherapy[J]. J Med Chem,2016,59(14):6595-6628. doi: 10.1021/acs.jmedchem.5b01461 [11] ANAND K, ZIEBUHR J, WADHWANI P, et al. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs[J]. Science,2003,300(5626):1763-1767. doi: 10.1126/science.1085658 [12] PATICK A K, BINFORD S L, BROTHERS M A, et al. <italic>In vitro</italic> antiviral activity of AG7088, a potent inhibitor of human rhinovirus 3C protease[J]. Antimicrob Agents Chemother,1999,43(10):2444-2450. doi: 10.1128/AAC.43.10.2444 [13] GHOSH A K, XI K, RATIA K, et al. Design and synthesis of peptidomimetic severe acute respiratory syndrome chymotrypsin-like protease inhibitors[J]. J Med Chem,2005,48(22):6767-6771. doi: 10.1021/jm050548m [14] GHOSH A K, XI K, GRUM-TOKARS V, et al. Structure-based design, synthesis, and biological evaluation of peptidomimetic SARS-CoV 3CLpro inhibitors[J]. Bioorg Med Chem Lett,2007,17(21):5876-5880. doi: 10.1016/j.bmcl.2007.08.031 [15] JAIN R P, PETTERSSON H I, ZHANG J M, et al. Synthesis and evaluation of keto-glutamine analogues as potent inhibitors of severe acute respiratory syndrome 3CLpro[J]. J Med Chem,2004,47(25):6113-6116. doi: 10.1021/jm0494873 [16] SHIE J J, FANG J M, KUO T H, et al. Inhibition of the severe acute respiratory syndrome 3CL protease by peptidomimetic alpha, beta-unsaturated esters[J]. Bioorg Med Chem,2005,13(17):5240-5252. doi: 10.1016/j.bmc.2005.05.065 [17] YANG S, CHEN S J, HSU M F, et al. Synthesis, crystal structure, structure-activity relationships, and antiviral activity of a potent SARS coronavirus 3CL protease inhibitor[J]. J Med Chem,2006,49(16):4971-4980. doi: 10.1021/jm0603926 [18] XUE X Y, YU H W, YANG H T, et al. Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design[J]. J Virol,2008,82(5):2515-2527. doi: 10.1128/JVI.02114-07 [19] PRIOR A M, KIM Y, WEERASEKARA S, et al. Design, synthesis, and bioevaluation of viral 3C and 3C-like protease inhibitors[J]. Bioorg Med Chem Lett,2013,23(23):6317-6320. doi: 10.1016/j.bmcl.2013.09.070 [20] ZHOU Y C, VEDANTHAM P, LU K, et al. Protease inhibitors targeting coronavirus and filovirus entry[J]. Antiviral Res,2015,116:76-84. doi: 10.1016/j.antiviral.2015.01.011 [21] KONNO H, WAKABAYASHI M, TAKANUMA D, et al. Design and synthesis of a series of serine derivatives as small molecule inhibitors of the SARS coronavirus 3CL protease[J]. Bioorg Med Chem,2016,24(6):1241-1254. doi: 10.1016/j.bmc.2016.01.052 [22] KONNO H, ONUMA T, NITANAI I, et al. Synthesis and evaluation of phenylisoserine derivatives for the SARS-CoV 3CL protease inhibitor[J]. Bioorg Med Chem Lett,2017,27(12):2746-2751. doi: 10.1016/j.bmcl.2017.04.056 [23] CHEN L L, LI J, LUO C, et al. Binding interaction of quercetin-3-beta-galactoside and its synthetic derivatives with SARS-CoV 3CL(pro): structure-activity relationship studies reveal salient pharmacophore features[J]. Bioorg Med Chem,2006,14(24):8295-8306. doi: 10.1016/j.bmc.2006.09.014 [24] YU M S, LEE J, LEE J M, et al. Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13[J]. Bioorg Med Chem Lett,2012,22(12):4049-4054. doi: 10.1016/j.bmcl.2012.04.081 [25] KIM D W, SEO K H, CURTIS-LONG M J, et al. Phenolic phytochemical displaying SARS-CoV papain-like protease inhibition from the seeds of <italic>Psoralea</italic> corylifolia[J]. J Enzyme Inhib Med Chem,2014,29(1):59-63. doi: 10.3109/14756366.2012.753591 [26] PARK J Y, KO J A, KIM D W, et al. Chalcones isolated from <italic>Angelica keiskei</italic> inhibit cysteine proteases of SARS-CoV[J]. J Enzyme Inhib Med Chem,2016,31(1):23-30. doi: 10.3109/14756366.2014.1003215 [27] PARK J Y, YUK H J, RYU H W, et al. Evaluation of polyphenols from <italic>Broussonetia papyrifera</italic> as coronavirus protease inhibitors[J]. J Enzyme Inhib Med Chem,2017,32(1):504-515. doi: 10.1080/14756366.2016.1265519 [28] WU C Y, KING K Y, KUO C J, et al. Stable benzotriazole esters as mechanism-based inactivators of the severe acute respiratory syndrome 3CL protease[J]. Chem Biol,2006,13(3):261-268. doi: 10.1016/j.chembiol.2005.12.008 [29] TURLINGTON M, CHUN A, TOMAR S, et al. Discovery of N-benzo[J]. Bioorg Med Chem Lett,2013,23(22):6172-6177. doi: 10.1016/j.bmcl.2013.08.112 [30] RAMAJAYAM R, TAN K P, LIU H G, et al. Synthesis and evaluation of pyrazolone compounds as SARS-coronavirus 3C-like protease inhibitors[J]. Bioorg Med Chem,2010,18(22):7849-7854. doi: 10.1016/j.bmc.2010.09.050 [31] KUMAR V, TAN K P, WANG Y M, et al. Identification, synthesis and evaluation of SARS-CoV and MERS-CoV 3C-like protease inhibitors[J]. Bioorg Med Chem,2016,24(13):3035-3042. doi: 10.1016/j.bmc.2016.05.013 [32] GHOSH A K, TAKAYAMA J, AUBIN Y, et al. Structure-based design, synthesis, and biological evaluation of a series of novel and reversible inhibitors for the severe acute respiratory syndrome-coronavirus papain-like protease[J]. J Med Chem,2009,52(16):5228-5240. doi: 10.1021/jm900611t [33] BÁEZ-SANTOS Y M, BARRAZA S J, WILSON M W, et al. X-ray structural and biological evaluation of a series of potent and highly selective inhibitors of human coronavirus papain-like proteases[J]. J Med Chem,2014,57(6):2393-2412. doi: 10.1021/jm401712t [34] ZHOU L, LIU Y, ZHANG W L, et al. Isatin compounds as noncovalent SARS coronavirus 3C-like protease inhibitors[J]. J Med Chem,2006,49(12):3440-3443. doi: 10.1021/jm0602357 [35] KEYAERTS E, VIJGEN L, MAES P, et al. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine[J]. Biochem Biophys Res Commun,2004,323(1):264-268. doi: 10.1016/j.bbrc.2004.08.085 [36] VINCENT M J, BERGERON E, BENJANNET S, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread[J]. Virol J,2005,2:69. doi: 10.1186/1743-422X-2-69 [37] DE WILDE A H, JOCHMANS D, POSTHUMA C C, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture[J]. Antimicrob Agents Chemother,2014,58(8):4875-4884. doi: 10.1128/AAC.03011-14 [38] CHEUNG N N, LAI K K, DAI J, et al. Broad-spectrum inhibition of common respiratory RNA viruses by a pyrimidine synthesis inhibitor with involvement of the host antiviral response[J]. J Gen Virol,2017,98(5):946-954. doi: 10.1099/jgv.0.000758 [39] NIU C Y, YIN J, ZHANG J M, et al. Molecular docking identifies the binding of 3-chloropyridine moieties specifically to the S1 pocket of SARS-CoV Mpro[J]. Bioorg Med Chem,2008,16(1):293-302. doi: 10.1016/j.bmc.2007.09.034 [40] ZHANG J M, HUITEMA C, NIU C Y, et al. Aryl methylene ketones and fluorinated methylene ketones as reversible inhibitors for severe acute respiratory syndrome (SARS) 3C-like proteinase[J]. Bioorg Chem,2008,36(5):229-240. doi: 10.1016/j.bioorg.2008.01.001 [41] JACOBS J, GRUM-TOKARS V, ZHOU Y, et al. Discovery, synthesis, and structure-based optimization of a series of N-(tert-butyl)-2-(N-arylamido)-2-(pyridin-3-yl) acetamides (ML188) as potent noncovalent small molecule inhibitors of the severe acute respiratory syndrome coronavirus (SARS-CoV) 3CL protease[J]. J Med Chem,2013,56(2):534-546. doi: 10.1021/jm301580n [42] GHOSH A K, GONG G L, GRUM-TOKARS V, et al. Design, synthesis and antiviral efficacy of a series of potent chloropyridyl ester-derived SARS-CoV 3CLpro inhibitors[J]. Bioorg Med Chem Lett,2008,18(20):5684-5688. doi: 10.1016/j.bmcl.2008.08.082 [43] CHEN L L, GUI C S, LUO X M, et al. Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication <italic>in vitro</italic>[J]. J Virol,2005,79(11):7095-7103. doi: 10.1128/JVI.79.11.7095-7103.2005 [44] CHEN L R, WANG Y C, LIN Y W, et al. Synthesis and evaluation of isatin derivatives as effective SARS coronavirus 3CL protease inhibitors[J]. Bioorg Med Chem Lett,2005,15(12):3058-3062. doi: 10.1016/j.bmcl.2005.04.027 [45] LU I L, MAHINDROO N, LIANG P H, et al. Structure-based drug design and structural biology study of novel nonpeptide inhibitors of severe acute respiratory syndrome coronavirus main protease[J]. J Med Chem,2006,49(17):5154-5161. doi: 10.1021/jm060207o [46] BACHA U, BARRILA J, GABELLI S B, et al. Development of broad-spectrum halomethyl ketone inhibitors against coronavirus main protease 3CL(pro)[J]. Chem Biol Drug Des,2008,72(1):34-49. doi: 10.1111/j.1747-0285.2008.00679.x [47] WANG L, BAO B B, SONG G Q, et al. Discovery of unsymmetrical aromatic disulfides as novel inhibitors of SARS-CoV main protease: Chemical synthesis, biological evaluation, molecular docking and 3D-QSAR study[J]. Eur J Med Chem,2017,137:450-461. doi: 10.1016/j.ejmech.2017.05.045 [48] CHO J H, BERNARD D L, SIDWELL R W, et al. Synthesis of cyclopentenyl carbocyclic nucleosides as potential antiviral agents against orthopoxviruses and SARS[J]. J Med Chem,2006,49(3):1140-1148. doi: 10.1021/jm0509750 [49] AGOSTINI M L, ANDRES E L, SIMS A C, et al. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease[J]. mBio,2018,9(2):e00221-e00218. [50] 乔欢, 孙超. 潜在抗冠状病毒药物瑞德西韦研究进展[J]. 中国新药与临床杂志, 2020, 39(3):141-145. [51] PETERS H L, JOCHMANS D, DE WILDE A H, et al. Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity[J]. Bioorg Med Chem Lett,2015,25(15):2923-2926. doi: 10.1016/j.bmcl.2015.05.039 [52] MÜLLER C, SCHULTE F W, LANGE-GRÜNWELLER K, et al. Broad-spectrum antiviral activity of the eIF4A inhibitor silvestrol against <italic>Corona</italic>- and picornaviruses[J]. Antiviral Res,2018,150:123-129. doi: 10.1016/j.antiviral.2017.12.010 [53] LEE H, REN J H, PESAVENTO R P, et al. Identification and design of novel small molecule inhibitors against MERS-CoV papain-like protease via high-throughput screening and molecular modeling[J]. Bioorg Med Chem,2019,27(10):1981-1989. doi: 10.1016/j.bmc.2019.03.050 [54] WANG M L, CAO R Y, ZHANG L K, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) <italic>in vitro</italic>[J]. Cell Res,2020,30(3):269-271. doi: 10.1038/s41422-020-0282-0 [55] LIU J, CAO R Y, XU M Y, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection <italic>in vitro</italic>[J]. Cell Discov,2020,6:16. [56] GAO J J, TIAN Z X, YANG X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies[J]. Biosci Trends,2020,14(1):72-73. doi: 10.5582/bst.2020.01047 [57] MEHRA M R, DESAI S S, RUSCHITZKA F, et al. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis[J]. The Lancet,2020. doi: 10.1016/S0140-6736(20)31180-6 [58] WANG Y M, ZHANG D Y, DU G H, et al. Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial[J]. Lancet,2020(20):31022-31029. [59] National Institute of Allergy and Infectious Diseases. NIH clinical trial shows Remdesivir accelerates recovery from advanced COVID-19[EB/OL]. (2020-04-29)[2020-05-10]. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19. [60] ZHOU P, YANG X L, WANG X G, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin[J]. Nature,2020,579(7798):270-273. doi: 10.1038/s41586-020-2012-7 [61] CHU C M, CHENG V C, HUNG I F, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings[J]. Thorax,2004,59(3):252-256. doi: 10.1136/thorax.2003.012658 [62] CAO B, WANG Y M, WEN D N, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19[J]. N Engl J Med,2020,382(19):1787-1799. doi: 10.1056/NEJMoa2001282