Hepatitis C Virus NS3/4A Protease Inhibitors

Abstract

Chronic hepatitis C virus infection is a global problem worldwide due to the lack of an effective therapy (the current standard of care treatment is effective in about 40-50% of the cases), and the difficulties in developing a protective vaccine. Chronic infection progresses to end-stage liver disease and liver failure in a considerable number of infected individuals. Once liver function is compromised, the only reliable therapeutic intervention is liver transplantation. Unfortunately, re-infection of the graft is unavoidable, and a new chronic hepatitis is early established in transplant recipients, that can result in graft loss. Thus, there is an urgent need for new, specifically targeted therapies for the treatment of HCV chronic infection. Among the viral proteins, the NS3/4A protease and the NS5b RNA-dependent RNA-polymerase, essential for the virus life cycle, have concentrated the efforts in the development of new antivirals, and some promising ones have already entered clinical trials. In particular, inhibitors of the HCV NS3/4A protease are the most advanced in clinical development. This review summarizes the available data for the most important HCV NS3/4A protease inhibitors in development, the most recent patents of these type of compounds, the envisioned options for future HCV therapies, and the eventual impact of HCV genetic variability on resistance to new NS3/4A protease inhibitors.

Docking Studies of Pakistani HCV NS3 Helicase: A Possible Antiviral Drug Target

“…Herein we describe an integrated strategy for identifying fragment inhibitors using computational techniques. Due to increase in HCV infection cases and lack of effective therapies, there is a need to develop specific compounds that can target the HCV [12]. Therefore, this study was planned to molecularly characterize the Pakistani HCV helicase protein.…”

Genetic diversity of NS3 protease from Brazilian HCV isolates and possible implications for therapy with direct-acting antiviral drugs

“…Therefore, the HCV NS3 protein is at present considered to not only be an attractive constituent for the production of an anti-HCV vaccine (Zeng et al 2009), but also an important target for the development of new therapeutic protease inhibitors (Enomoto et al 2009). To date, several specific NS3-4A S protease inhibitors, such as VX-950, SCH6, SCH503034, ITMN-191 and TMC435350, have been designed and are currently being evaluated in clinical trials (López-Labrador 2008). However, given the high level of variability of HCV, which is a result of the error-prone nature of RNA-dependent RNA polymerase, variants resistant to a number of protease inhibitors have been identified (Peres-da-Silva et al 2010, Vermehren & Sarrazin 2011) and represent a current challenge for therapy with DAAs.…”

HCV Infection and NS-3 Serine Protease Inhibitors

“…After the success of protease inhibitors in the treatment of human-immunodeficiency virus-1 (HIV) infection, it is thought that development of a specific inhibitors of NS3 protease activity would be an attractive target for new anti-HCV drugs [10,16]. The inhibition of NS3/4A protease will interfere with the viral life cycle and restore the pathways of innate immunity [17].…”

“…This combination treatment can be used to decline HCV infection cases and people who do not respond to monotherapy. Due to increase in HCV infection cases and lack of effective therapies, there is a need to develop specific compounds that can target important factors of the HCV life cycle [10].…”