Novel azapeptide inhibitors of hepatitis C virus serine protease.

Azapeptides are known inhibitors of several serine and cysteine proteases. In seeking different classes of inhibitors for the HCV serine protease, a series of novel azapeptide-based inhibitors were investigated which incorporated noncleavable P1/P1' aza-amino acyl residues. Extensive SAR studies around the P1/P1' aza-amino acyl fragment resulted in the identification of potent and selective inhibitors. Using NMR studies, we have shown that this series of inhibitors bind in a noncovalent competitive fashion to the NS3 protease active site. The bound conformation of one of these new azapeptide-based inhibitors was determined using the transfer NOE technique. Incorporation of these new aza-amino acyl functionalities in the P1 position provided a handle to probe for new interactions in the S' region of the enzyme.