Design, synthesis and biological evaluation of covalent peptidomimetic 3CL protease inhibitors containing nitrile moiety

Mengwei Zhu; Tiantian Fu; Mengyuan You; Junyuan Cao; Hanxi Yang; Xinyao Chen; Qiumeng Zhang; Yechun Xu; Xiangrui Jiang; Leike Zhang; Haixia Su; Yan Zhang; Jingshan Shen

doi:10.1016/j.bmc.2023.117316

Design, synthesis and biological evaluation of covalent peptidomimetic 3CL protease inhibitors containing nitrile moiety

Bioorg Med Chem. 2023 May 3:87:117316. doi: 10.1016/j.bmc.2023.117316. Epub 2023 May 8.

Authors

Mengwei Zhu¹, Tiantian Fu¹, Mengyuan You², Junyuan Cao³, Hanxi Yang⁴, Xinyao Chen⁵, Qiumeng Zhang⁶, Yechun Xu⁷, Xiangrui Jiang⁶, Leike Zhang⁸, Haixia Su⁹, Yan Zhang¹⁰, Jingshan Shen⁶

Affiliations

¹ College of Pharmacy, An Hui University of Traditional Chinese Medicine, Hefei 230012, China; Yangtze Delta Drug Advanced Research Institute and Yangtze Delta Pharmaceutical College, Nantong 226133, China.
² School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
³ State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei 430071, China; Hubei Jiangxia Laboratory, Wuhan 430200, China.
⁴ College of Chemistry, Zhengzhou University, Zhengzhou 450001, China.
⁵ Yangtze Delta Drug Advanced Research Institute and Yangtze Delta Pharmaceutical College, Nantong 226133, China; Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
⁶ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁷ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁸ State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei 430071, China; Hubei Jiangxia Laboratory, Wuhan 430200, China. Electronic address: zhangleike@wh.iov.cn.
⁹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: suhaixia1@simm.ac.cn.
¹⁰ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: zhang_yan@simm.ac.cn.

Abstract

In this paper, a series of peptidomimetic SARS-CoV-2 3CL protease inhibitors with new P2 and P4 positions were synthesized and evaluated. Among these compounds, 1a and 2b exhibited obvious 3CL^pro inhibitory activities with IC₅₀ of 18.06 nM and 22.42 nM, respectively. 1a and 2b also showed excellent antiviral activities against SARS-CoV-2 in vitro with EC₅₀ of 313.0 nM and 170.2 nM, respectively, the antiviral activities of 1a and 2b were 2- and 4-fold better than that of nirmatrelvir, respectively. In vitro studies revealed that these two compounds had no significant cytotoxicity. Further metabolic stability tests and pharmacokinetic studies showed that the metabolic stability of 1a and 2b in liver microsomes was significantly improved, and 2b had similar pharmacokinetic parameters to that of nirmatrelvir in mice.

Keywords: 3CL protease; COVID-19; Nirmatrelvir; Peptidomimetic inhibitors; SARS-CoV-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents / pharmacology
COVID-19*
Mice
Nitriles
Peptidomimetics* / pharmacology
Protease Inhibitors / pharmacology
SARS-CoV-2

Substances

Protease Inhibitors
Peptidomimetics
Nitriles
Antiviral Agents