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

Xiangrui Jiang, Haixia Su, Weijuan Shang, Feng Zhou, Yan Zhang, Wenfeng Zhao, Qiumeng Zhang, Hang Xie, Lei Jiang, Tianqing Nie, Feipu Yang, Muya Xiong, Xiaoxing Huang, Minjun Li, Ping Chen, Shaoping Peng, Gengfu Xiao, Hualiang Jiang, Renhong Tang (), Leike Zhang (), Jingshan Shen () and Yechun Xu ()
Additional contact information
Xiangrui Jiang: Chinese Academy of Sciences
Haixia Su: Chinese Academy of Sciences
Weijuan Shang: Chinese Academy of Sciences
Feng Zhou: State Key Laboratory of Neurology and Oncology Drug Development
Yan Zhang: Chinese Academy of Sciences
Wenfeng Zhao: Chinese Academy of Sciences
Qiumeng Zhang: Chinese Academy of Sciences
Hang Xie: Chinese Academy of Sciences
Lei Jiang: Simcere Zaiming Pharmaceutical Co., Ltd
Tianqing Nie: Chinese Academy of Sciences
Feipu Yang: Chinese Academy of Sciences
Muya Xiong: Chinese Academy of Sciences
Xiaoxing Huang: Simcere Zaiming Pharmaceutical Co., Ltd
Minjun Li: Chinese Academy of Sciences
Ping Chen: Jiangsu Simcere Pharmaceutical Co., Ltd
Shaoping Peng: State Key Laboratory of Neurology and Oncology Drug Development
Gengfu Xiao: Chinese Academy of Sciences
Hualiang Jiang: Chinese Academy of Sciences
Renhong Tang: State Key Laboratory of Neurology and Oncology Drug Development
Leike Zhang: Chinese Academy of Sciences
Jingshan Shen: Chinese Academy of Sciences
Yechun Xu: Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract 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 (3CLpro) 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 3CLpro with an enthalpy-driven thermodynamic binding signature. Multiple enzymatic assays reveal that simnotrelvir is a potent pan-CoV 3CLpro 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.

Date: 2023
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DOI: 10.1038/s41467-023-42102-y

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