Structural Basis for the Inhibition of Coronaviral Main Proteases by a Benzothiazole-Based Inhibitor

Viruses. 2022 Sep 18;14(9):2075. doi: 10.3390/v14092075.

Abstract

The ongoing spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused hundreds of millions of cases and millions of victims worldwide with serious consequences to global health and economies. Although many vaccines protecting against SARS-CoV-2 are currently available, constantly emerging new variants necessitate the development of alternative strategies for prevention and treatment of COVID-19. Inhibitors that target the main protease (Mpro) of SARS-CoV-2, an essential enzyme that promotes viral maturation, represent a key class of antivirals. Here, we showed that a peptidomimetic compound with benzothiazolyl ketone as warhead, YH-53, is an effective inhibitor of SARS-CoV-2, SARS-CoV, and MERS-CoV Mpros. Crystal structures of Mpros from SARS-CoV-2, SARS-CoV, and MERS-CoV bound to the inhibitor YH-53 revealed a unique ligand-binding site, which provides new insights into the mechanism of inhibition of viral replication. A detailed analysis of these crystal structures defined the key molecular determinants required for inhibition and illustrate the binding mode of Mpros from other coronaviruses. In consideration of the important role of Mpro in developing antivirals against coronaviruses, insights derived from this study should add to the design of pan-coronaviral Mpro inhibitors that are safer and more effective.

Keywords: YH-53; coronavirus; inhibitor; main protease; warhead.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry
  • Benzothiazoles / pharmacology
  • COVID-19 Drug Treatment*
  • Coronavirus 3C Proteases
  • Cysteine Endopeptidases / metabolism
  • Humans
  • Ketones
  • Ligands
  • Middle East Respiratory Syndrome Coronavirus*
  • Peptide Hydrolases
  • Peptidomimetics*
  • Protease Inhibitors / chemistry
  • SARS-CoV-2

Substances

  • Antiviral Agents
  • Benzothiazoles
  • Ketones
  • Ligands
  • Peptidomimetics
  • Protease Inhibitors
  • Peptide Hydrolases
  • Cysteine Endopeptidases
  • Coronavirus 3C Proteases

Grants and funding

This research was funded by the National Natural Science Foundation of China (Grant No. 81974514 and 31770795) and the Jiangxi Province Natural Science Foundation (Grant No. 20181ACB20014). J.L. was supported by Gannan Medical University (QD201910), Jiangxi Natural Science Foundation for Distinguished Young Scholars (20212ACB216001), Jiangxi Key Research and Development Program (20203BBG73063), and Jiangxi “Double Thousand Plan (jxsq2019101064)”. J.Z. was supported by the Thousand Young Talents Program of China and the CAS “Light of West China” Program (2021). P.J.M. was supported by the Foreign Talent project of Jiangxi Province. This work was also supported by Ganzhou COVID-19 Emergency Research Project (2020.17), Major science and technology programs of Ganzhou City (2020.67), and Ganzhou Zhanggong District COVID-19 prevention and control key research projects (2020.67). P.Z. were supported by Shenzhen COVID-19 Special funding 2022036 (Grant No. JSGG20220606140801003).