Non-Covalent Inhibitors of SARS-CoV-2 Papain-Like Protease (PLpro): In Vitro and In Vivo Antiviral Activity.
Ganga Reddy VelmaZhengnan ShenCameron HolbergJiqiang FuFarinaz SoleymaniLaura CooperOmar Lozano RamosDivakar IndukuriSoumya Reddy MuskuPavel RychetskySteve SlilatyZuomei LiKiira RatiaLijun RongDominik SchentenRui XiongGregory R J ThatcherPublished in: Journal of medicinal chemistry (2024)
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.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- immune response
- mouse model
- liver failure
- copy number
- signaling pathway
- gene expression
- coronavirus disease
- quantum dots
- dendritic cells
- cancer therapy
- respiratory failure
- risk assessment
- human health
- extracorporeal membrane oxygenation
- drug delivery
- molecular dynamics simulations