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
Y517GP2 is critical for biological activity, while T519GP2, E100GP1, and D522GP2 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.