mk-7009 and Liver-Neoplasms

mk-7009 has been researched along with Liver-Neoplasms* in 1 studies

Other Studies

1 other study(ies) available for mk-7009 and Liver-Neoplasms

Article	Year
Differential efficacy of protease inhibitors against HCV genotypes 2a, 3a, 5a, and 6a NS3/4A protease recombinant viruses. Gastroenterology, 2011, Volume: 141, Issue:3 The hepatitis C virus (HCV) genotype influences efficacy of interferon (IFN)-based therapy. HCV protease inhibitors are being licensed for treatment of genotype 1 infection. Because there are limited or no data on efficacy against HCV genotypes 2-7, we aimed at developing recombinant infectious cell culture systems expressing genotype-specific nonstructural (NS) protein 3 protease (NS3P).. Viability of J6/JFH1-based recombinants with genotypes 1-7 NS3P/NS4A was evaluated in Huh7.5 human hepatoma cells. Adaptive mutations were identified in reverse genetic studies. Efficacy of lead compound linear protease inhibitors VX-950 (telaprevir) and SCH503034 (boceprevir) and macrocyclic inhibitors TMC435350, ITMN-191 (danoprevir), and MK-7009 (vaniprevir) was determined in high-throughput infection assays.. For genotype(isolate) 2a(J6), 3a(S52), 5a(SA13), and 6a(HK6a), we developed culture systems producing supernatant infectivity titers of 3.5-4.0 log₁₀ focus forming units/mL. Against 2a(J6), 5a(SA13), and 6a(HK6a), all inhibitors showed similar efficacy; macrocyclic inhibitors had ~10-fold greater potency than linear inhibitors. However, compared with 2a recombinant J6/JFH1, efficacy against 3a(S52) was 16- to 70-fold lower for macrocyclic inhibitors and 2- to 7-fold lower for linear inhibitors. Testing of additional genotype 2a and 3a isolates showed that these differences were genotype specific. The resistance of 3a isolates was similar to J6/JFH1 with engineered resistance mutations originally observed for genotype 1 patients. In contrast, we found similar efficacy of NS5A inhibitor BMS-790052 and interferon-alfa2.. Novel HCV culture systems with genotype specific NS3P/NS4A revealed similar efficacy of protease inhibitors against genotypes 2a, 5a, and 6a and comparatively low but varying efficacy against genotype 3a isolates. These systems will facilitate genotype-specific studies of HCV protease inhibitors and of viral resistance. Topics: Carcinoma, Hepatocellular; Carrier Proteins; Cell Line, Tumor; Cyclopropanes; Genotype; Hepacivirus; Hepatitis C; Humans; Indoles; Intracellular Signaling Peptides and Proteins; Isoindoles; Lactams; Lactams, Macrocyclic; Leucine; Liver Neoplasms; Molecular Sequence Data; Oligopeptides; Proline; Protease Inhibitors; Sulfonamides; Treatment Outcome; Viral Nonstructural Proteins	2011

Article

Year

Differential efficacy of protease inhibitors against HCV genotypes 2a, 3a, 5a, and 6a NS3/4A protease recombinant viruses.

Gastroenterology, 2011, Volume: 141, Issue:3

The hepatitis C virus (HCV) genotype influences efficacy of interferon (IFN)-based therapy. HCV protease inhibitors are being licensed for treatment of genotype 1 infection. Because there are limited or no data on efficacy against HCV genotypes 2-7, we aimed at developing recombinant infectious cell culture systems expressing genotype-specific nonstructural (NS) protein 3 protease (NS3P).. Viability of J6/JFH1-based recombinants with genotypes 1-7 NS3P/NS4A was evaluated in Huh7.5 human hepatoma cells. Adaptive mutations were identified in reverse genetic studies. Efficacy of lead compound linear protease inhibitors VX-950 (telaprevir) and SCH503034 (boceprevir) and macrocyclic inhibitors TMC435350, ITMN-191 (danoprevir), and MK-7009 (vaniprevir) was determined in high-throughput infection assays.. For genotype(isolate) 2a(J6), 3a(S52), 5a(SA13), and 6a(HK6a), we developed culture systems producing supernatant infectivity titers of 3.5-4.0 log₁₀ focus forming units/mL. Against 2a(J6), 5a(SA13), and 6a(HK6a), all inhibitors showed similar efficacy; macrocyclic inhibitors had ~10-fold greater potency than linear inhibitors. However, compared with 2a recombinant J6/JFH1, efficacy against 3a(S52) was 16- to 70-fold lower for macrocyclic inhibitors and 2- to 7-fold lower for linear inhibitors. Testing of additional genotype 2a and 3a isolates showed that these differences were genotype specific. The resistance of 3a isolates was similar to J6/JFH1 with engineered resistance mutations originally observed for genotype 1 patients. In contrast, we found similar efficacy of NS5A inhibitor BMS-790052 and interferon-alfa2.. Novel HCV culture systems with genotype specific NS3P/NS4A revealed similar efficacy of protease inhibitors against genotypes 2a, 5a, and 6a and comparatively low but varying efficacy against genotype 3a isolates. These systems will facilitate genotype-specific studies of HCV protease inhibitors and of viral resistance.

Topics: Carcinoma, Hepatocellular; Carrier Proteins; Cell Line, Tumor; Cyclopropanes; Genotype; Hepacivirus; Hepatitis C; Humans; Indoles; Intracellular Signaling Peptides and Proteins; Isoindoles; Lactams; Lactams, Macrocyclic; Leucine; Liver Neoplasms; Molecular Sequence Data; Oligopeptides; Proline; Protease Inhibitors; Sulfonamides; Treatment Outcome; Viral Nonstructural Proteins

2011