β-Amino acid substitutions and structure-based CoMFA modeling of hepatitis C virus NS3 protease inhibitors Original Research Article

In an effort to develop a new type of HCV NS3 peptidomimetic inhibitor, a series of tripeptide inhibitors incorporating a mix of α- and β-amino acids has been synthesized. To understand the structural implications of β-amino acid substitution, the P1, P2, and P3 positions of a potent tripeptide scaffold were scanned and combined with carboxylic acid and acyl sulfonamide C-terminal groups. Inhibition was evaluated and revealed that the structural changes resulted in a loss in potency compared with the α-peptide analogues. However, several compounds exhibited μM potency. Inhibition data were compared with modeled ligand–protein binding poses to understand how changes in ligand structure affected inhibition potency. The P3 position seemed to be the least sensitive position for β-amino acid substitution. Moreover,