Abstract
Background: Proteolytic cleavage of inactive pathogen proteins by furin is critical for their entry into human cells, and thus furin cleavage of the SARS-CoV-2 spike protein was identified as a prerequisite for virus binding and the subsequent infection of human cells in the recent COVID-19 pandemic. We report a water-aware structure-based protease inhibitor design study. Methods: Our efforts focused on the biological evaluation of small molecule inhibitors that emerged from a conserved water-aware virtual screening campaign of a library of compounds that shared structural or physicochemical properties with known furin inhibitors exhibiting newly recognized binding modes. Results: We identified a novel small-molecule furin protease inhibitor with a 1,3-thiazol-2-ylaminosulfonyl scaffold. Namely, the compound N-[4-(1,3-thiazol-2-ylaminosulfonyl)phenyl]-3-{(E)-5-[(2-methoxyphenyl)methylene]-4-oxo-2-thioxo-1,3-thiazolidin-3-yl}propionamide showed an IC(50) value of 17.58 μM, comparable to other published inhibitors. Conclusions: This compound could represent a starting point for the further design and development of non-peptidic, small-molecule furin inhibitors that could assist in furin cleavage studies and coronaviral pathogenesis.