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

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

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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