Different Types of P1 Residues in Peptide-Based Inhibitors of Hepatitis C Virus Full-Length NS3 Protease

Abstract

In a project aimed at the design and synthesis of inhibitors to the hepatitis C virus (HCV) NS3 serine protease, peptides containing different types of P1 residues were compared: 1) pentafluoroethyl ketones, since substrate-based peptides containing electrophilic groups in the P1 position are classical inhibitors of serine proteases; 2) tetrazoles, since HCV NS3 protease is uniquely inhibited by its N-terminal cleavage products [1] and tetrazoles are known metabolically stable bioisosteres for carboxylic acids; 3) ketotetrazoles, since peptide α-ketoacids work as electrophilic inhibitors of the HCV NS3 protease [2] and oc-ketotetrazoles should serve as α-ketoacid bioisosteres and; 4) carboxylic acids, as reference compounds.