Home Products Cited in Publications Worldwide Non-Covalent Inhibitors of SARS-CoV-2 Papain-Like Protease (PLpro): In Vitro and In Vivo Antiviral Activity
Ganga Reddy Velma; Zhengnan Shen; Cameron Holberg; Jiqiang Fu; Farinaz Soleymani; Laura Cooper; Omar Lozano Ramos; Divakar Indukuri; Soumya Reddy Musku; Pavel Rychetsky; Steve Slilaty; Zuomei Li; Kiira Ratia; Lijun Rong; Dominik Schenten; Rui Xiong; Gregory R. J Thatcher
DOI:10.1021/acs.jmedchem.4c00378 PMID:39102360
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.