Non-Covalent Inhibitors of SARS-CoV-2 Papain-Like Protease (PLpro): In Vitro and In Vivo Antiviral Activity

  • J Med Chem. 2024 Aug 5. doi: 10.1021/acs.jmedchem.4c00378.
Ganga Reddy Velma  1 ,  Zhengnan Shen  1 ,  Cameron Holberg  1 ,  Jiqiang Fu  1 ,  Farinaz Soleymani  2 ,  Laura Cooper  3 ,  Omar Lozano Ramos  1 ,  Divakar Indukuri  1 ,  Soumya Reddy Musku  1 ,  Pavel Rychetsky  1 ,  Steve Slilaty  4 ,  Zuomei Li  4 ,  Kiira Ratia  5 ,  Lijun Rong  3 ,  Dominik Schenten  6 ,  Rui Xiong  1 ,  Gregory R J Thatcher  1  2
Affiliations
  • 1. Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, University of Arizona, Tucson 85721, Arizona, United States.
  • 2. Department of Chemistry & Biochemistry, Colleges of Science and Medicine, University of Arizona, Tucson 85721, Arizona, United States.
  • 3. Department of Microbiology, College of Medicine, University of Illinois at Chicago (UIC), Chicago 60612, Illinois, United States.
  • 4. Sunshine Biopharma Inc, 333 Las Olas Way, CU4 Suite 433, Fort Lauderdale 33301, Florida, United States.
  • 5. Research Resources Center, University of Illinois at Chicago (UIC), Chicago 60612, Illinois, United States.
  • 6. Department of Immunology, College of Medicine, University of Arizona, Tucson 85721, Arizona, United States.
PMID: 39102360 DOI: 10.1021/acs.jmedchem.4c00378
Abstract

The SARS-CoV-2 papain-like protease (PLpro), essential for viral processing and immune response disruption, is a promising target for treating acute Infection of SARS-CoV-2. To date, there have been no reports of PLpro inhibitors with both submicromolar potency and animal model efficacy. To address the challenge of PLpro's featureless active site, a noncovalent inhibitor library with over 50 new analogs was developed, targeting the PLpro active site by modulating the BL2-loop and engaging the BL2-groove. Notably, compounds 42 and 10 exhibited strong Antiviral effects and were further analyzed pharmacokinetically. 10, in particular, showed a significant lung accumulation, up to 12.9-fold greater than plasma exposure, and was effective in a mouse model of SARS-CoV-2 Infection, as well as against several SARS-CoV-2 variants. These findings highlight the potential of 10 as an in vivo chemical probe for studying PLpro inhibition in SARS-CoV-2 Infection.

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