Dichlorophenylpyridine-Based Molecules Inhibit Furin through an Induced-Fit Mechanism.

ABSTRACT: Inhibitors of the proprotein convertase furin might serve as broad-spectrum antiviral therapeutics. High cellular potency and antiviral activity against acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported for (3,5-dichlorophenyl)pyridine-derived furin inhibitors. Here we characterized the binding mechanism of this inhibitor class using structural, biophysical, and biochemical methods. We established a MALDI-TOF-MS-based furin activity assay, determined IC₅₀ values, and solved X-ray structures of (3,5-dichlorophenyl)pyridine-derived compounds in complex with furin. The inhibitors induced a substantial conformational rearrangement of the active-site cleft by exposing a central buried tryptophan residue. These changes formed an extended hydrophobic surface patc

SUBMITTER: Dahms SO 

PROVIDER: S-EPMC9016704 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature