benzofurans and telaprevir

Direct-acting antiviral has replaced pegylated interferon-α and ribavirin-based treatment in the treatment of chronic hepatitis C virus (HCV) infection. While interferon-α is immune modulating and causes lymphopenia, interferon-free regimens seem to be well-tolerated. This study aimed to compare T-cell homeostasis before, during, and after HCV treatment with or without interferon-α in patients with chronic HCV infection. A total of 20 patients with chronic HCV infection were treated with pegylated interferon-α and ribavirin, and six patients were treated with an interferon-free regimen. All patients were treated for a minimum of 12 weeks. Interferon-α treatment caused an increase in the density of the receptor for IL-7 (IL-7Rα) during treatment, while interferon-free regimens caused a decrease in IL-7Rα density. After a sustained viral response, proportions of IL-7Rα+ T cells and IL-7Rα density decreased compared to prior treatment values. Finally, a proportion of CD8+ effector memory was lower while proportion of apoptotic T cells was higher after sustained virologic response compared to prior treatment. Despite lymphopenia during interferon, alterations in T-cell homeostasis during treatment were relatively similar in patients receiving interferon-based treatment and in patients receiving interferon-free treatment, and alterations during and after treatment seem to illustrate a reduced need for high levels of T cells aimed at controlling infection.

Topics: Adult; Aged; Amides; Antiviral Agents; Apoptosis; Benzofurans; Carbamates; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cyclopropanes; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Interferon-alpha; Interleukin-7 Receptor alpha Subunit; Lipopolysaccharides; Lymphocyte Count; Lymphopenia; Male; Middle Aged; Oligopeptides; Polyethylene Glycols; Proline; Prospective Studies; Quinoxalines; Recombinant Proteins; Ribavirin; Sulfonamides

In vitro, telaprevir selects subtype-specific resistance pathways for hepatitis C virus GT-1a and GT-1b, as described to have occurred in patients. In GT-1a, the HCV-796 resistance mutation C316Y has low replication capacity (7%) that can be compensated for by the emergence of the mutation L392F or M414T, resulting in an increase in replication levels of > or = 10-fold.

Topics: Antiviral Agents; Benzofurans; Drug Resistance, Viral; Genotype; Hepacivirus; Humans; Kinetics; Microbial Sensitivity Tests; Oligopeptides; Protease Inhibitors; Sulfonamides; Viral Nonstructural Proteins; Virus Replication

A new series of potent antitumor and antiviral benzofuran derivatives was synthesized by the reaction of the furochromone-6-carboxaldehydes 1 and 2 with different heterocyclic amines to yield the benzofuran-5-carbonyl derivatives 4-11. The synthesized compounds 1, 3-11 were tested against twelve different human cancer cell lines and all of the compounds were more potent than the comparative standards. The HIV inhibitory activity of the tested compounds 1, 3-11 showed that they have higher potency than Atevirdine. Moreover, compound 6 was significantly potent with wider therapeutic index. The HIV-1 RT inhibitory activity showed that compounds 10, 11, 3 and 4 were notably potent but with lower therapeutic index than Atevirdine. The HCV NS3-4A protease inhibitor activity of the tested compounds revealed that they have weaker potency and less therapeutic index than VX-950, although compounds 1, 4, 9 and 6, respectively exhibited significant activity.

Topics: Antineoplastic Agents; Antiviral Agents; Benzofurans; Cell Line, Tumor; Chemistry, Pharmaceutical; Drug Design; Drug Screening Assays, Antitumor; HIV Reverse Transcriptase; Humans; Inhibitory Concentration 50; Models, Chemical; Oligopeptides; Piperazines