{"title":"sars - cov - 23clpro高效非共价抑制剂的研制","authors":"Ningke Hou, Lei Shuai, Lijing Zhang, Xuping Xie, Kaiming Tang, Yunkai Zhu, Yin Yu, Wenyi Zhang, Qiaozhu Tan, Gongxun Zhong, Zhiyuan Wen, Chong Wang, Xijun He, Hong Huo, Haishan Gao, You Xu, Jing Xue, Chen Peng, Jing Zou, Craig Schindewolf, Vineet Menachery, Wenji Su, Youlang Yuan, Zuyuan Shen, Rong Zhang, Shuofeng Yuan, Hongtao Yu, Pei-Yong Shi*, Zhigao Bu*, Jing Huang* and Qi Hu*, ","doi":"10.1021/acscentsci.2c01359","DOIUrl":null,"url":null,"abstract":"<p >The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, noncovalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC<sub>50</sub> values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment.</p><p >A novel oral noncovalent inhibitor of 3C-like protease, named WU-04, was developed as a promising drug candidate for COVID-19 treatment.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"9 2","pages":"217–227"},"PeriodicalIF":12.7000,"publicationDate":"2023-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9885526/pdf/","citationCount":"5","resultStr":"{\"title\":\"Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro\",\"authors\":\"Ningke Hou, Lei Shuai, Lijing Zhang, Xuping Xie, Kaiming Tang, Yunkai Zhu, Yin Yu, Wenyi Zhang, Qiaozhu Tan, Gongxun Zhong, Zhiyuan Wen, Chong Wang, Xijun He, Hong Huo, Haishan Gao, You Xu, Jing Xue, Chen Peng, Jing Zou, Craig Schindewolf, Vineet Menachery, Wenji Su, Youlang Yuan, Zuyuan Shen, Rong Zhang, Shuofeng Yuan, Hongtao Yu, Pei-Yong Shi*, Zhigao Bu*, Jing Huang* and Qi Hu*, \",\"doi\":\"10.1021/acscentsci.2c01359\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, noncovalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC<sub>50</sub> values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment.</p><p >A novel oral noncovalent inhibitor of 3C-like protease, named WU-04, was developed as a promising drug candidate for COVID-19 treatment.</p>\",\"PeriodicalId\":10,\"journal\":{\"name\":\"ACS Central Science\",\"volume\":\"9 2\",\"pages\":\"217–227\"},\"PeriodicalIF\":12.7000,\"publicationDate\":\"2023-01-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9885526/pdf/\",\"citationCount\":\"5\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Central Science\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acscentsci.2c01359\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Central Science","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acscentsci.2c01359","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro
The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, noncovalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC50 values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment.
A novel oral noncovalent inhibitor of 3C-like protease, named WU-04, was developed as a promising drug candidate for COVID-19 treatment.
期刊介绍：
ACS Central Science publishes significant primary reports on research in chemistry and allied fields where chemical approaches are pivotal. As the first fully open-access journal by the American Chemical Society, it covers compelling and important contributions to the broad chemistry and scientific community. "Central science," a term popularized nearly 40 years ago, emphasizes chemistry's central role in connecting physical and life sciences, and fundamental sciences with applied disciplines like medicine and engineering. The journal focuses on exceptional quality articles, addressing advances in fundamental chemistry and interdisciplinary research.
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