Hepatitis C virus (HCV) proteases: structure, function and inhibition strategies

Hepatitis C virus (HCV) is a bloodborne, hepatotropic RNA virus and a serious global health burden, infecting over 50 million people worldwide, with the majority residing in low- and middle-income countries (LMICs), that significantly contributes to chronic liver diseases like cirrhosis and hepatocellular carcinoma. While no vaccines are available for HCV yet, over the years the success of direct-acting antivirals (DAAs) has been contributing with improved cure rates among treatment-naïve and treatment-experienced patients. However, many challenges remain due to undiagnosed infections and limited access to DAAs in LMICs. Thus, understanding of the molecular biology of HCV is pivotal in driving therapeutic advances, particularly the characterization of its two major proteases: the NS2/3 protease, a cysteine protease responsible for the first cleavage event of the polyprotein; and the NS3/4A protease, a serine protease that cleaves the remainder of the HCV genome. These proteases have been extensively studied as drug targets, although there is still much to learn. The NS3/4A protease has been a validated target for the development of DAAs, with several FDA-approved drugs in recent years. Yet, many challenges remain, as the genetic diversity of HCV has been leading to the emergence of drug-resistant strains that require the administration of the costly pan-genotypic DAAs. In this chapter we explore the structure and functions of NS2/3 and NS3/4A in the viral life cycle, how DAAs engage such targets and which mutations drive resistance. We conclude by discussing future and even less explored approaches in hopes of contributing to the current HCV drug development scenario.