2. Academic Validation
  3. Structural basis for the inhibition of coronaviral main proteases by ensitrelvir

Structural basis for the inhibition of coronaviral main proteases by ensitrelvir

  • Structure. 2023 Jun 27;S0969-2126(23)00207-1. doi: 10.1016/j.str.2023.06.010.
Cheng Lin 1,  Haihai Jiang 2,  Wenwen Li 3,  Pei Zeng 4,  Xuelan Zhou 4,  Jin Zhang 5,  Jian Li 6
Affiliations

Affiliations

  • 1 College of Pharmaceutical Sciences, Gannan Medical University, Ganzhou 341000, China.
  • 2 School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China.
  • 3 Shenzhen Crystalo Biopharmaceutical Co., Ltd., Shenzhen 518118, China; Jiangxi Jmerry Biopharmaceutical Co., Ltd., Ganzhou 341000, China.
  • 4 Jiangxi Jmerry Biopharmaceutical Co., Ltd., Ganzhou 341000, China.
  • 5 School of Basic Medical Sciences, Nanchang University, Nanchang 330031, China. Electronic address: zhangxiaokong@hotmail.com.
  • 6 College of Pharmaceutical Sciences, Gannan Medical University, Ganzhou 341000, China. Electronic address: rmsl_2040@163.com.
PMID: 37421945 DOI: 10.1016/j.str.2023.06.010
Abstract

Main protease (Mpro) is a highly conserved cysteine protease that plays a vital role in the replication of coronaviruses, making it an attractive pan-coronaviral therapeutic target. Ensitrelvir (S-217622), developed by Shionogi, is the first orally active non-covalent, non-peptidic SARS-CoV-2 Mpro inhibitor, which also displays Antiviral efficacy against Other human coronaviruses as well as SARS-CoV-2 variants of concern (VOCs) and variants of interest (VOIs). Here, we report the crystal structures of the main proteases from SARS-CoV-2, SARS-CoV-2 VOC/VOIs, SARS-CoV, MERS-CoV, and HCoV-NL63 bound to the inhibitor S-217622. A detailed analysis of these structures illuminates key structural determinants essential for inhibition and elucidates the binding modes of the main proteases from different coronaviruses. Given the importance of the main protease for the treatment of coronaviral Infection, structural insights obtained from this study could accelerate the design of novel antivirals with broad-spectrum efficacy against different human coronaviruses.

Keywords

S-217622; SARS-CoV-2; SARS-CoV-2 variant; Structural basis; main protease.

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