bi-201335 and danoprevir

The current standard of care for patients with chronic hepatitis C virus (HCV) infection is pegylated interferon alfa in combination with ribavirin. Treatment duration and efficacy depend heavily on HCV genotype. A sustained virologic response (SVR) is achieved only in approximately 40% of patients. Side effects of the current standard of care often make adherence to therapy difficult, further reducing the chance for an SVR. Numerous patient-related and virus-related factors can determine response to treatment. Nonresponders are a large proportion of the current HCV-infected population, and the number of patients with HCV infection is growing, necessitating newer therapies with higher efficacy and potentially fewer side effects. A new era of direct acting antiviral (DAA) compounds has emerged. The first 2 protease inhibitors for HCV infection, telaprevir and boceprevir, are coming to market in 2011. Other protease compounds in development include TMC-435, vaniprevir, BI-201335, BMS-650032, and danoprevir. The numerous other therapies that have potential in the treatment of HCV infection include nucleoside inhibitors, non-nucleoside inhibitors, NS5A inhibitors, DAA combinations, therapeutic vaccines, human monoclonal antibodies, immune modifiers, and interferon lambda.

Topics: Aminoisobutyric Acids; Cyclopropanes; Drug Resistance, Viral; Drug Therapy, Combination; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 3-Ring; Humans; Indoles; Isoindoles; Lactams; Lactams, Macrocyclic; Leucine; Oligopeptides; Proline; Quinolines; Simeprevir; Sulfonamides; Thiazoles; Treatment Outcome; Viral Load; Virus Replication

Infection with the hepatitis C virus (HCV) is a major cause of chronic liver disease and a leading indication of liver transplantations worldwide. The current standard of care for chronic hepatitis C is a combination of pegylated interferon-α and ribavirin that is effective in slightly more than half of cases and is associated with significant side effects. The first directly acting antivirals recently reached the US market, but will have shortcomings that should in part be overcome by the second-wave PIs that are in development. This article gives an overview of the compounds that will soon be available.

Topics: Aminoisobutyric Acids; Antiviral Agents; Carrier Proteins; Cyclopropanes; Hepatitis C; Heterocyclic Compounds, 3-Ring; Humans; Intracellular Signaling Peptides and Proteins; Isoindoles; Lactams; Lactams, Macrocyclic; Leucine; Oligopeptides; Proline; Protease Inhibitors; Quinolines; Simeprevir; Sulfonamides; Thiazoles; Viral Nonstructural Proteins

Hepatitis C virus (HCV) is a serious cause of liver inflammation, cirrhosis and the development of hepatocellular carcinoma. Its NS3/4A serine protease functions to cleave a specific peptide bond, which is an important step in HCV replication. Thus the NS3/4A protease has become one of the main drug-targets in the design and development of anti-HCV agents. Unfortunately, high mutation rates in HCV have been reported due to the lack of RNA proofreading activity resulting in drug resistance. Herein, all-atom molecular dynamics simulations were employed to understand and illustrate the effects of the NS3/4A D168V mutation on faldaprevir (FDV) and danoprevir (DNV) binding efficiency. The D168V mutation was shown to interrupt the hydrogen bonding network of Q80R155D168R123 embedded in the extended S2 and partial S4 subsites of the NS3 protein and as a result the R123 side chain was displaced and moved out from the binding pocket. By means of MM/PBSA and MM/GBSA binding free energy calculations, the FDV and DNV binding affinities were shown to be significantly reduced by ∼10-15 kcal mol

Topics: Amino Acid Substitution; Aminoisobutyric Acids; Binding Sites; Catalytic Domain; Codon; Cyclopropanes; Drug Resistance, Viral; Hepacivirus; Humans; Hydrogen Bonding; Isoindoles; Lactams; Lactams, Macrocyclic; Leucine; Models, Molecular; Molecular Conformation; Mutation; Oligopeptides; Proline; Protein Binding; Quinolines; Sulfonamides; Thiazoles; Viral Nonstructural Proteins