Abstract:COVID-19, a global pandemic outbreak that has rapidly swept across the world, has posed an unprecedented threat to human health. No effective drug is against the SARS-CoV-2 virus is currently available on the market, thus placing the control and prevention of this pandemic at a significant disadvantage. Therefore, targeted drugs against SARS-CoV-2 have been a focus of many researchers. SARS-CoV-2, itself expressing 29 proteins, simultaneously interacts with various host proteins, thus leading to a large number of potential selectable drug targets. Among them, the structures of several protein targets have already been analyzed, and some drugs have been designed and selected on this basis. For example, the nucleotide analogs remdesivir and sofosbuvir that target SARS-CoV-2 RNA polymerase, several iIrreversible inhibitors that target Mpro, and the peptide compound EK1 that targets the spike protein.This article provides a summary of the R&D process, based on structural biology methods, of targeted drugs against SARS-CoV-2.
刘雪晴, 严汉池. 基于结构生物学指导的SARS-CoV-2靶向药设计筛选[J]. 中国人兽共患病学报, 2021, 37(1): 1-5.
LIU Xue-qing, YAN Han-chi. The design and selection of targeted drugs against SARS-CoV-2 on the basis of structural biology. Chinese Journal of Zoonoses, 2021, 37(1): 1-5.
[1] Xia S,Liu M,Wang C,et al.Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion[J]. Cell Res, 2020, 30(4):343-355. DOI: 10.1038/s41422-020-0305-x [2] Zhou P,Yang X,Wang X,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 [3] Chan JF,Yuan S,Kok KH,et al.A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster[J]. Lancet, 2020, 395(10223):514-523. DOI: 10.1016/S0140-6736(20)30154-9 [4] Gao Y,Yan L,Huang Y,et al.Structure of the RNA-dependent RNA polymerase from COVID-19 virus[J]. Science, 2020, 368(6492):779-782. DOI: 10.1126/science.abb7498 [5] Gane EJ,Stedman CA,Hyland RH,et al.Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C[J]. N Engl J Med, 2013, 368(1):34-44. DOI: 10.1126/science.abb7498 [6] Wang M,Cao R,Zhang L,et al.Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro[J]. Cell Res, 2020, 30(3):269-271. DOI: 10.1038/s41422-020-0282-0 [7] Jin Z,Du X,Xu Y,et al.Structure of Mpro from COVID-19 virus and discovery of its inhibitors[J]. Nature, 582(7811):289-293. DOI: 10.1038/s41586-020-2223-y [8] Yang H,Xie W,Xue X,et al.Design of wide-spectrum inhibitors targeting coronavirus main proteases[J]. Plos Biol, 2005, 3(10):e324. DOI: 10.1371/journal.pbio.0030324 [9] Xue X,Yu H,Yang H,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 [10] Ren Z,Yan L,Zhang N,et al.The newly emerged SARS-Like coronavirus HCoV-EMC also has an "Achilles’ heel": current effective inhibitor targeting a 3C-like protease[J]. Protein Cell, 2013, 4(4):248-250. DOI: 10.1007/s13238-013-2841-3 [11] Wang F,Chen C,Tan W,et al.Structure of main protease from human coronavirus NL63: insights for wide spectrum anti-coronavirus drug design[J]. Sci Rep, 2016, 6:22677. DOI: 10.1038/srep22677 [12] Kil J,Lobarinas E,Spankovich C,et al.Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial[J]. Lancet, 2017, 390(10098):969-979. DOI: 10.1016/S0140-6736(17)31791-9 [13] Zhang L,Lin D,Sun X,et al.Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved alpha-ketoamide inhibitors[J]. Science,2020,368(6489):409-412. DOI: 10.1126/science.abb3405 [14] Wrapp D,Wang N,Corbett KS,et al.Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation[J]. Science, 2020, 367(6483):1260-1263. DOI: 10.1126/science.abb2507 [15] Walls AC,Park YJ,Tortorici MA,et al.Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein[J]. Cell, 2020,181(2):281-292. DOI: 10.1016/j.cell.2020.02.058 [16] Mathieu C,Porotto M,Figueira TN,et al.Fusion inhibitory lipopeptides engineered for prophylaxis of Nipah virus in primates[J]. J Infect Dis. 2018, 218(2):218-227. DOI: 10.1093/infdis/jiy152 [17] Zhang L,Jackson CB,Mou H,et al.The D614G mutation in the SARS-CoV-2 spike protein reduces S1 shedding and increases infectivity[J]. BioRixv, 2020. DOI: 10.1101/2020.06.12.148726 [18] Carl Z,Jonathan C. Bad news wrapped in protein: inside the coronavirus genome[EB/OL]. (2020-04-03)[2020-04-07].https://www.nytimes.com/interactive/2020/04/03/science/coronavirus-genome-bad-news-wrapped-in-protein.html [19] Kawase M,Shirato K,Hoek LVD,et al.Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry[J]. J Virol, 2012, 86(12):6537-6545. DOI: 10.1128/JVI.00094-12