Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model

Science. 2024 Mar 29;383(6690):1434-1440. doi: 10.1126/science.adm9724. Epub 2024 Mar 28.

Abstract

The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. The SARS-CoV-2 papain-like protease (PLpro) is a promising but challenging drug target. We designed and synthesized 85 noncovalent PLpro inhibitors that bind to a recently discovered ubiquitin binding site and the known BL2 groove pocket near the S4 subsite. Leads inhibited PLpro with the inhibitory constant Ki values from 13.2 to 88.2 nanomolar. The co-crystal structures of PLpro with eight leads revealed their interaction modes. The in vivo lead Jun12682 inhibited SARS-CoV-2 and its variants, including nirmatrelvir-resistant strains with EC50 from 0.44 to 2.02 micromolar. Oral treatment with Jun12682 improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 infection mouse model, suggesting that PLpro inhibitors are promising oral SARS-CoV-2 antiviral candidates.

MeSH terms

  • Administration, Oral
  • Animals
  • COVID-19 Drug Treatment*
  • COVID-19*
  • Coronavirus Papain-Like Proteases* / antagonists & inhibitors
  • Coronavirus Papain-Like Proteases* / chemistry
  • Coronavirus Protease Inhibitors* / administration & dosage
  • Coronavirus Protease Inhibitors* / chemistry
  • Coronavirus Protease Inhibitors* / pharmacology
  • Crystallography, X-Ray
  • Disease Models, Animal
  • Drug Design*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • SARS-CoV-2* / drug effects
  • SARS-CoV-2* / enzymology
  • Structure-Activity Relationship
  • Viral Load / drug effects

Substances

  • Coronavirus Papain-Like Proteases
  • papain-like protease, SARS-CoV-2
  • Coronavirus Protease Inhibitors

Supplementary concepts

  • SARS-CoV-2 variants