Linear and Macrocyclic Hepatitis C Virus Protease Inhibitors: Inhibitor Design and Macrocyclization Strategies for HCV Protease and Related Targets

Abstract

Enormous progress has been made towards an all-oral, very highly sustained viral response (considered a cure) treatment of hepatitis C. Key ingredients of these therapies are hepatitis C virus (HCV) protease inhibitors (PIs). The first generation linear and covalent PIs, telaprevir and boceprevir, were discovered through the enzyme substrate-based approach and are being followed by a second generation of non-covalent PIs. Many of these are macrocycles, as exemplified by the recently FDA-approved simeprevir. This chapter will detail the science successfully employed in both the substrate-based and inhibitor macrocyclization approaches. Additionally, as HCV PI C-terminal motifs develop critical contacts with the enzyme catalytic Ser139 and adjacent sites, this chapter discusses the mechanistic and structural details of such interactions for both the reversible covalent ketoamide as well as non-covalent sulfonamide and carboxylic acid moieties. Efforts to explore a cyclic boronate motif in various linear and cyclic HCV PIs in search of both Ser139-specific and opportunistic enzyme–inhibitor interactions are also summarized herein. In addition, key clinical and marketed PIs are described, including extensive references to primary literature. Finally, this chapter briefly covers key macrocyclic inhibitors of HCV RNA-dependent RNA polymerase NS5B and selected non-HCV macrocyclic protease inhibitors in order to provide additional insights into the successful design of macrocyclic drugs.