Crystal structures of main proteases of SARS-CoV-2 variants bound to a benzothiazole-based inhibitor

Acta Biochim Biophys Sin (Shanghai). 2023 Jun 26;55(8):1257-1264. doi: 10.3724/abbs.2023053.

Abstract

Main protease (M pro) serves as an indispensable factor in the life cycle of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as its constantly emerging variants and is therefore considered an attractive target for antiviral drug development. Benzothiazole-based inhibitors targeting M pro have recently been investigated by several groups and proven to be promising leads for coronaviral drug development. In the present study, we determine the crystal structures of a benzothiazole-based inhibitor, YH-53, bound to M pro mutants from SARS-CoV-2 variants of concern (VOCs) or variants of interest (VOIs), including K90R (Beta, B.1.351), G15S (Lambda, C.37), Y54C (Delta, AY.4), M49I (Omicron, BA.5) and P132H (Omicron, B.1.1.529). The structures show that the benzothiazole group in YH-53 forms a C-S covalent bond with the sulfur atom of catalytic residue Cys145 in SARS-CoV-2 M pro mutants. Structural analysis reveals the key molecular determinants necessary for interaction and illustrates the binding mode of YH-53 to these mutant M pros. In conclusion, structural insights from this study offer more information to develop benzothiazole-based drugs that are broader spectrum, more effective and safer.

Keywords: SARS-CoV-2; YH-53; benzothiazole; inhibitor; main protease; variant.

MeSH terms

  • Antiviral Agents / pharmacology
  • Benzothiazoles
  • COVID-19*
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism
  • Humans
  • Molecular Docking Simulation
  • Protease Inhibitors / chemistry
  • SARS-CoV-2* / genetics
  • SARS-CoV-2* / metabolism

Substances

  • Protease Inhibitors
  • Cysteine Endopeptidases
  • Antiviral Agents
  • Benzothiazoles

Supplementary concepts

  • SARS-CoV-2 variants

Grants and funding

This work was supported by the grants from the Gannan Medical University (No. QD201910), the Jiangxi Natural Science Foundation for Distinguished Young Scholars (No. 20212ACB216001), the Jiangxi Key Research and Development Program (No. 20203BBG73063), the Jiangxi “Double Thousand Plan (No. jxsq2019101064)” to J.L., the Thousand Young Talents Program of China and the CAS “Light of West China” Program (2021) to J.Z., the Natural Science Foundation of Jiangxi Province (No. 20224BAB216004) to H.J., and the Shanghai Science and Technology Plan Project (No. 21ZR1471800) to Q.W.