Structural basis for the inhibition of coronaviral main proteases by PF-00835231

Acta Biochim Biophys Sin (Shanghai). 2024 Jul 29;56(12):1813-1822. doi: 10.3724/abbs.2024122.

Abstract

The main protease (M pro) of coronaviruses plays a key role in viral replication, thus serving as a hot target for drug design. PF-00835231 is a promising inhibitor of SARS-CoV-2 M pro. Here, we report the inhibitory potency of PF-00835231 against SARS-CoV-2 M pro and seven M pro mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) from SARS-CoV-2 variants. The results confirm that PF-00835231 has broad-spectrum inhibition against various coronaviral M pros. In addition, the crystal structures of SARS-CoV-2 M pro, SARS-CoV M pro, MERS-CoV M pro, and seven SARS-CoV-2 M pro mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) in complex with PF-00835231 are solved. A detailed analysis of these structures reveals key determinants essential for inhibition and elucidates the binding modes of different coronaviral M pros. Given the importance of the main protease for the treatment of coronaviral infection, structural insights into M pro inhibition by PF-00835231 can accelerate the design of novel antivirals with broad-spectrum efficacy against different human coronaviruses.

Keywords: PF-00835231; coronavirus; crystal structure; inhibition; main protease.

MeSH terms

  • Coronavirus 3C Proteases* / antagonists & inhibitors
  • Coronavirus 3C Proteases* / chemistry
  • Coronavirus 3C Proteases* / genetics
  • Coronavirus Protease Inhibitors* / chemistry
  • Coronavirus Protease Inhibitors* / pharmacology
  • Crystallography, X-Ray
  • Indoles* / chemistry
  • Indoles* / pharmacology
  • Leucine* / chemistry
  • Leucine* / pharmacology
  • Mutation
  • Protein Domains
  • Pyrrolidinones* / chemistry
  • Pyrrolidinones* / pharmacology
  • Structure-Activity Relationship

Substances

  • lufotrelvir
  • Indoles
  • Leucine
  • Pyrrolidinones
  • 3C-like protease, SARS coronavirus
  • Coronavirus 3C Proteases
  • Coronavirus Protease Inhibitors

Grants and funding

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 82360701, 32360223, and 32271260), the Jiangxi Provincial Natural Science Foundation (Nos. 20212ACB216001, 20224BAB216004, 20232BAB205025, and 20224ACB206046), the CAS “Light of West China” Program (No. xbzg-zdsys-202005), the Jiangxi Key Research and Development Program (No. 20203BBG73063), the Jiangxi Double Thousand Plan (No. jxsq2019101064), and the foundation of Gannan Medical University (No. QD201910).