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Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir

文献类型：期刊论文

作者Jiang, Xiangrui1,2; Su, Haixia1; Shang, Weijuan3; Zhou, Feng4,5; Zhang, Yan1; Zhao, Wenfeng1; Zhang, Qiumeng1; Xie, Hang1,6; Jiang, Lei5; Nie, Tianqing1,6
刊名NATURE COMMUNICATIONS
出版日期2023-10-13
卷号14期号:1页码:15
DOI10.1038/s41467-023-42102-y
英文摘要The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the great demand for developing effective therapeutic agents. Here, we report the development of an orally bioavailable SARS-CoV-2 3C-like protease (3CL(pro)) inhibitor, namely simnotrelvir, and its preclinical evaluation, which lay the foundation for clinical trials studies as well as the conditional approval of simnotrelvir in combination with ritonavir for the treatment of COVID-19. The structure-based optimization of boceprevir, an approved HCV protease inhibitor, leads to identification of simnotrelvir that covalently inhibits SARS-CoV-2 3CL(pro) with an enthalpy-driven thermodynamic binding signature. Multiple enzymatic assays reveal that simnotrelvir is a potent pan-CoV 3CL(pro) inhibitor but has high selectivity. It effectively blocks replications of SARS-CoV-2 variants in cell-based assays and exhibits good pharmacokinetic and safety profiles in male and female rats and monkeys, leading to robust oral efficacy in a male mouse model of SARS-CoV-2 Delta infection in which it not only significantly reduces lung viral loads but also eliminates the virus from brains. The discovery of simnotrelvir thereby highlights the utility of structure-based development of marked protease inhibitors for providing a small molecule therapeutic effectively combatting human coronaviruses.
WOS关键词DRUG ; DISCOVERY ; ENTHALPY ; BINDING ; MODEL ; SARS
资助项目National Natural Science Foundation of China[22277130] ; National Natural Science Foundation of China[U22A20379] ; Shanghai Science and Technology Committee grant[22YF1457300] ; Shanghai Institute of Materia Medica, CAS[CASIMM0120234003] ; Shanghai Institute of Materia Medica, CAS[SIMM010120] ; Shanghai Institute of Materia Medica, CAS[SIMM010118] ; Wuhan Institute of Virology, CAS[2022QNTJ-01] ; Qiusuo Outstanding Youth Project of Lingang Laboratory[LG-QS-202205-02]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001117712600024
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/309596]  
专题新药研究国家重点实验室
通讯作者Tang, Renhong; Zhang, Leike; Shen, Jingshan; Xu, Yechun
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Ctr Biosafety Mega Sci, Wuhan Inst Virol, State Key Lab Virol, Wuhan 430071, Peoples R China
4.State Key Lab Neurol & Oncol Drug Dev, Nanjing 210023, Peoples R China
5.Simcere Zaiming Pharmaceut Co Ltd, Shanghai 200000, Peoples R China
6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
7.Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai Synchrotron Radiat Facil, Shanghai 201210, Peoples R China
8.Jiangsu Simcere Pharmaceut Co Ltd, Nanjing 210023, Peoples R China
9.Hubei Jiangxia Lab, Wuhan 430200, Peoples R China
10.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
推荐引用方式
GB/T 7714		 Jiang, Xiangrui,Su, Haixia,Shang, Weijuan,et al. Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir[J]. NATURE COMMUNICATIONS,2023,14(1):15.
APA Jiang, Xiangrui.,Su, Haixia.,Shang, Weijuan.,Zhou, Feng.,Zhang, Yan.,...&Xu, Yechun.(2023).Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir.NATURE COMMUNICATIONS,14(1),15.
MLA Jiang, Xiangrui,et al."Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir".NATURE COMMUNICATIONS 14.1(2023):15.

入库方式： OAI收割

来源：上海药物研究所

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