From Diarylsulfides to Diarylamines: New Ebola Virus Entry Inhibitors with Improved Metabolic Stability

The persistence of current outbreaks of Ebola virus (EBOV) disease and challenges in the production and administration of approved vaccines and treatments highlight the continuous exploration of new therapeutic alternatives. In this context, this work focuses on optimizing diarylsulfide hits previously identified as EBOV entry inhibitors. Structural modifications resulted in diarylamine derivatives, with confirmed antiviral activity against replicative EBOV and significantly improved metabolic stability compared to diarylsulfides. Using different techniques, the EBOV glycoprotein (EBOV-GP) was identified as the target of these compounds. Residue Y517_GP2 is critical for biological activity, while T519_GP2, E100_GP1, and D522_GP2 also contribute to ligand binding. Furthermore, the binding of the derivatives to EBOV-GP has been shown to destabilize the complex with the virus receptor NPC1. In short, a new family of diarylsulfides and diarylamines with antiviral activity against EBOV has been developed, and their mechanism of action has been deciphered, paving the way for future pharmaceutical development.