Thiol-Reactive or Redox-Active: Revising a Repurposing Screen Led to a New Invalidation Pipeline and Identified a True Noncovalent Inhibitor Against Papain-like Protease from SARS-CoV-2.

ABSTRACT: The SARS-CoV-2 papain-like protease PLpro has multiple roles in the viral replication cycle, related to both its polypeptide cleavage function and its ability to antagonize the host immune response. Targeting the PLpro function is recognized as a promising mechanism to modulate viral replication, while supporting host immune responses. However, the development of PLpro-specific inhibitors remains challenging. Comprehensive investigations utilizing enzymatic, binding studies, and cellular assays revealed the previously reported inhibitors to act in an unspecific manner. At present, GRL-0617 and its derivatives remain the best-validated compounds with demonstrated antiviral activity in cells and in mouse models. In this study, we refer to the pitfalls of the redox sensitivity of PLpro. Using

SUBMITTER: Kuzikov M 

PROVIDER: S-EPMC11729419 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature