2. Academic Validation
  3. Structure-Based Design of Covalent SARS-CoV-2 Papain-like Protease Inhibitors

Structure-Based Design of Covalent SARS-CoV-2 Papain-like Protease Inhibitors

  • J Med Chem. 2024 Nov 28;67(22):20399-20420. doi: 10.1021/acs.jmedchem.4c01872.
Bin Tan 1,  Xueying Liang 2,  Ahmadullah Ansari 3 4,  Prakash Jadhav 1,  Haozhou Tan 1,  Kan Li 1,  Francesc Xavier Ruiz 3 4,  Eddy Arnold 3 4,  Xufang Deng 2 5,  Jun Wang 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854, United States.
  • 2 Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, Oklahoma 74078, United States.
  • 3 Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854, United States.
  • 4 Department of Chemistry and Chemical Biology, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854, United States.
  • 5 Oklahoma Center for Respiratory and Infectious Diseases, Oklahoma State University, Stillwater, Oklahoma 74078, United States.
PMID: 39499574 DOI: 10.1021/acs.jmedchem.4c01872
Abstract

The COVID-19 pandemic is caused by SARS-CoV-2, a highly transmissible and pathogenic RNA betacoronavirus. Like Other RNA viruses, SARS-CoV-2 continues to evolve with or without drug selection pressure, and many variants have emerged since the beginning of the pandemic. The papain-like protease, PLpro, is a cysteine protease that cleaves viral polyproteins as well as ubiquitin and ISG15 modifications from host proteins. Leveraging our recently discovered Val70Ub binding site in PLpro, we designed covalent PLpro inhibitors by connecting cysteine reactive warheads to the biarylphenyl PLpro inhibitors via flexible linkers. Several leads displayed potent enzymatic inhibition (IC50 = 0.1-0.3 μM) and Antiviral activity (EC50 = 0.09-0.96 μM). Fumaramide inhibitors Jun13567 (15), Jun13728 (16), and Jun13714 (18) showed favorable in vivo pharmacokinetic properties with intraperitoneal injection. The X-ray crystal structure of PLpro with Jun13567 (15) validated our design strategy, revealing covalent conjugation between the catalytic Cys111 and the fumaramide warhead. The results suggest these covalent PLpro inhibitors are promising SARS-CoV-2 Antiviral drug candidates.

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