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

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.
Bin Tan # 1,  Xiaoming Zhang # 2,  Ahmadullah Ansari # 3 4,  Prakash Jadhav # 1,  Haozhou Tan 1,  Kan Li 1,  Ashima Chopra 3 4,  Alexandra Ford 5,  Xiang Chi 2,  Francesc Xavier Ruiz 3 4,  Eddy Arnold 3 4,  Xufang Deng 2 6,  Jun Wang 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA.
  • 2 Department Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA.
  • 3 Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA.
  • 4 Department of Chemistry and Chemical Biology, Rutgers, the State University of New Jersey, Piscataway, NJ 08854, USA.
  • 5 Department of Veterinary Pathobiology, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA.
  • 6 Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, OK 74078, USA.
  • # Contributed equally.
PMID: 38547259 DOI: 10.1126/science.adm9724
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.

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