HCV NS3/4A protease inhibitors and the road to effective direct-acting antiviral therapies

Abstract

Hepatitis C virus (HCV) currently infects over 185 million individuals around the world. Its persistence causes infected individuals to enter a chronic phase where their condition can lead to several different outcomes of liver disease. HCV therapies are becoming highly efficient and well tolerated due to improved understanding of the HCV biology and to the discovery of antivirals targeting essential viral functions. The NS3 protein with its co-factor NS4A forms a serine protease (NS3/4A protease) that is indispensable for the maturation of HCV polyprotein. The NS3/4A protease was identified as a prime antiviral drug target. Its exploration led to the development of peptidomimetic inhibitors based on substrates and N-terminal products and to the rapid selection of drug candidates. Ciluprevir (BILN 2061) was the first NS3/4A protease inhibitors in clinical trials and it established the proof-of-concept in humans for a novel class of selective anti-HCV agents specifically designed to inhibit an essential viral enzyme. The inclusion of protease inhibitors with the standard of care therapy established the first major therapeutic advancement against HCV infection. In conjunction with other classes of anti-HCV agents, these inhibitors contributed to the revolution of all-oral interferon-free combination therapies. This chapter provides a historical perspective of the past 25 years in the validation of NS3/4A protease as an important drug target and in the rationale behind inhibitor design that led to the development of promising HCV antiviral drugs for the treatment of HCV infection.