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

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

  • bioRxiv. 2023 Dec 3:2023.12.01.569653. doi: 10.1101/2023.12.01.569653.
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 Deprtment 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.
PMID: 38076941 DOI: 10.1101/2023.12.01.569653
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. In this study, we designed and synthesized 85 noncovalent PLpro inhibitors that bind to the newly discovered Val70Ub site and the known BL2 groove pocket. Potent compounds inhibited PLpro with inhibitory constant Ki values from 13.2 to 88.2 nM. 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 μM. Oral treatment with Jun12682 significantly improved survival and reduced lung viral loads and lesions in a SARS-CoV-2 Infection mouse model, suggesting PLpro inhibitors are promising oral SARS-CoV-2 Antiviral candidates.

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