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

• Published in: Journal of medicinal chemistry 2024-08, Vol.67 (16), p.13681-13702
• Main Authors: Velma, Ganga Reddy, Shen, Zhengnan, Holberg, Cameron, Fu, Jiqiang, Soleymani, Farinaz, Cooper, Laura, Ramos, Omar Lozano, Indukuri, Divakar, Musku, Soumya Reddy, Rychetsky, Pavel, Slilaty, Steve, Li, Zuomei, Ratia, Kiira, Rong, Lijun, Schenten, Dominik, Xiong, Rui, J Thatcher, Gregory R.
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c00378

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.