{"title":"发现带丙烯酸酯弹头的 SARS-CoV-2 3CL 蛋白酶强效共价抑制剂。","authors":"","doi":"10.1016/j.bmcl.2024.129942","DOIUrl":null,"url":null,"abstract":"<div><p>COVID-19 has caused severe consequences in terms of public health and economy worldwide since its outbreak in December 2019. SARS-CoV-2 3C-like protease (3CL<sup>pro</sup>), crucial for the viral replications, is an attractive target for the development of antiviral drugs. In this study, several kinds of Michael acceptor warheads were utilized to hunt for potent covalent inhibitors against 3CL<sup>pro</sup>. Meanwhile, novel 3CL<sup>pro</sup> inhibitors with the P3-3,5-dichloro-4-(2-(dimethylamino)ethoxy)phenyl moiety were designed and synthesized which may form salt bridge with residue Glu166. Among them, two compounds <strong>12b</strong> and <strong>12c</strong> exhibited high inhibitory activities against SARS-CoV-2 3CL<sup>pro</sup>. Further investigations suggested that <strong>12b</strong> with an acrylate warhead displayed potent activity against HCoV-OC43 (EC<sub>50</sub> = 97 nM) and SARS-CoV-2 replicon (EC<sub>50</sub> = 45 nM) and low cytotoxicity (CC<sub>50</sub> > 10 μM) in Huh7 cells. Taken together, this study devised two series of 3CL<sup>pro</sup> inhibitors and provided the potent SARS-CoV-2 3CL<sup>pro</sup> inhibitor (<strong>12b</strong>) which may be used for treating coronavirus infections.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5000,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0960894X24003445/pdfft?md5=19f89b6b0937e4a9b795af4ea6a699dd&pid=1-s2.0-S0960894X24003445-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Discovery of the potent covalent inhibitor with an acrylate warhead for SARS-CoV-2 3CL protease\",\"authors\":\"\",\"doi\":\"10.1016/j.bmcl.2024.129942\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>COVID-19 has caused severe consequences in terms of public health and economy worldwide since its outbreak in December 2019. SARS-CoV-2 3C-like protease (3CL<sup>pro</sup>), crucial for the viral replications, is an attractive target for the development of antiviral drugs. In this study, several kinds of Michael acceptor warheads were utilized to hunt for potent covalent inhibitors against 3CL<sup>pro</sup>. Meanwhile, novel 3CL<sup>pro</sup> inhibitors with the P3-3,5-dichloro-4-(2-(dimethylamino)ethoxy)phenyl moiety were designed and synthesized which may form salt bridge with residue Glu166. Among them, two compounds <strong>12b</strong> and <strong>12c</strong> exhibited high inhibitory activities against SARS-CoV-2 3CL<sup>pro</sup>. Further investigations suggested that <strong>12b</strong> with an acrylate warhead displayed potent activity against HCoV-OC43 (EC<sub>50</sub> = 97 nM) and SARS-CoV-2 replicon (EC<sub>50</sub> = 45 nM) and low cytotoxicity (CC<sub>50</sub> > 10 μM) in Huh7 cells. Taken together, this study devised two series of 3CL<sup>pro</sup> inhibitors and provided the potent SARS-CoV-2 3CL<sup>pro</sup> inhibitor (<strong>12b</strong>) which may be used for treating coronavirus infections.</p></div>\",\"PeriodicalId\":256,\"journal\":{\"name\":\"Bioorganic & Medicinal Chemistry Letters\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2024-08-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S0960894X24003445/pdfft?md5=19f89b6b0937e4a9b795af4ea6a699dd&pid=1-s2.0-S0960894X24003445-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0960894X24003445\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0960894X24003445","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Discovery of the potent covalent inhibitor with an acrylate warhead for SARS-CoV-2 3CL protease
COVID-19 has caused severe consequences in terms of public health and economy worldwide since its outbreak in December 2019. SARS-CoV-2 3C-like protease (3CLpro), crucial for the viral replications, is an attractive target for the development of antiviral drugs. In this study, several kinds of Michael acceptor warheads were utilized to hunt for potent covalent inhibitors against 3CLpro. Meanwhile, novel 3CLpro inhibitors with the P3-3,5-dichloro-4-(2-(dimethylamino)ethoxy)phenyl moiety were designed and synthesized which may form salt bridge with residue Glu166. Among them, two compounds 12b and 12c exhibited high inhibitory activities against SARS-CoV-2 3CLpro. Further investigations suggested that 12b with an acrylate warhead displayed potent activity against HCoV-OC43 (EC50 = 97 nM) and SARS-CoV-2 replicon (EC50 = 45 nM) and low cytotoxicity (CC50 > 10 μM) in Huh7 cells. Taken together, this study devised two series of 3CLpro inhibitors and provided the potent SARS-CoV-2 3CLpro inhibitor (12b) which may be used for treating coronavirus infections.
期刊介绍：
Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.
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