Telaprevir: A Novel NS3/4 Protease Inhibitor for the Treatment of Hepatitis C

Abstract

Hepatitis C virus (HCV) infection affects millions of people worldwide; however, standard therapy with peginterferon and ribavirin has resulted in suboptimal responses. Thus, new anti-HCV drugs with novel mechanisms of action are being studied. In particular, new drugs are being developed that target the NS3/4A protease complex. We evaluated the literature on telaprevir, a new, oral, covalent, reversible NS3/4A HCV protease inhibitor. A MEDLINE search (January 1996-July 2011) was performed to identify relevant clinical trials, and abstracts from hepatology and human immunodeficiency virus (HIV) conferences were reviewed. In large clinical trials, the addition of telaprevir to peginterferon and ribavirin resulted in high sustained virologic response rates in both treatment-naïve and treatment-experienced patients infected with HCV genotype 1. Clinical data with telaprevir in the HIV-HCV coinfected population are emerging, as well as data on potential drug-drug interactions with this agent. Preliminary data describe the resistance profile of telaprevir; however, more information is needed in this evolving area. Telaprevir's most common adverse events included rash, pruritis, and anemia. Based on available data, this new anti-HCV drug will likely be widely used and may revolutionize the treatment of HCV-infected individuals.

In Silico Screening on the Three-dimensional Model of the Plasmodium vivax SUB1 Protease Leads to the Validation of a Novel Anti-parasite Compound

“…Anti-proteases have indeed changed the course of the epidemic of AIDS, and equivalent efficiency is expected in the treatment of hepatitis C (6). Over the last decades, Plasmodium proteases have been extensively studied and shown to play a role in hydrolysis of host erythrocyte hemoglobin in the parasite food vacuole (7)(8)(9), maturation of proteins for export into the host erythrocyte (10 -13), or in the egress and subsequent invasion of merozoites (14).…”

“…To take advantage of the improved model accuracy when several structural templates are used simultaneously (26), we selected from the Protein Data Bank (PDB) 6 a set of structures from homologs of the PvSUB1 and PfSUB1 catalytic domains. We considered only the most similar PDB entries associated with a blast e-value lower than 0.001 (27) To propose a reliable multiple sequence alignment of these templates with PfSUB1 and PvSUB1 catalytic domains, we also used additional protein sequences in the alignment step.…”

“…Briefly, 3-week-old Swiss mice were inoculated intraperitoneally with 2⅐10 6 parasitized red blood cells and randomly allocated to six groups of five mice. Cpd2 dissolved in 70:30 v/v Tween 80/ethanol (Sigma) and diluted 10-fold in sterile water was administered in 100, 66, or 33 mg/kg dose per mouse.…”

Discovery and Development of Telaprevir (Incivek™) – A Protease Inhibitor to Treat Hepatitis C Infection

“…The results from different phases of clinical trials of telaprevir have been recently described [7,24,25].…”

TGF-β1 polymorphism 509 C>T is associated with an increased risk for hepatocellular carcinoma in HCV-infected patients

“…Hepatitis C virus (HCV) is a small, enveloped, positive-sense single-stranded RNA virus that causes acute and often chronic hepatitis (Choo et al, 1989). Currently, an estimated 3% of the world's population, approximately 130-210 million people, is infected with HCV (Klibanov et al, 2011). Chronic HCV infection is a leading cause of progressive liver fibrosis and cirrhosis in up to 20% of patients; approximately 10-20% of cirrhotic patients may develop HCC within 5 years (Chiaramonte et al, 1999).…”