ABSTRACT Type III phosphatidylinositol-4-kinase beta (PI4KIIIβ) was previously implicated in hepatitis C virus (HCV) replication by small interfering RNA (siRNA) depletion and was therefore proposed as a novel cellular target for the treatment of hepatitis C. Medicinal chemistry efforts identified highly selective PI4KIIIβ inhibitors that potently inhibited the replication of genotype 1a and 1b HCV replicons and genotype 2a virus in vitro . Replicon cells required more than 5 weeks to reach low levels of 3- to 5-fold resistance, suggesting a high resistance barrier to these cellular targets. Extensive in vitro profiling of the compounds revealed a role of PI4KIIIβ in lymphocyte proliferation. Previously proposed functions of PI4KIIIβ in insulin secretion and the regulation of several ion channels were not perturbed with these inhibitors. Moreover, PI4KIIIβ inhibitors were not generally cytotoxic as demonstrated across hundreds of cell lines and primary cells. However, an unexpected antiproliferative effect in lymphocytes precluded their further development for the treatment of hepatitis C.
Tommasi R合作论文数2Thohan S合作论文数2Raman P合作论文数2Puyang X合作论文数2McKeever U合作论文数2Gaither L A合作论文数2Drumm J合作论文数2Ding J合作论文数2Dennehy M合作论文数2Borawski J合作论文数2Brigitte Wiedmann合作论文数2Matthew J. Lamarche合作论文数Department of Chemistry, University of Pennsylvania2K Lin合作论文数1K Wagner合作论文数1Xiong X合作论文数1Jiang X合作论文数1Gao J合作论文数1Dobler M合作论文数1Bose A合作论文数1
Richard A. Colvin合作论文数Center for Immunology and Inflammatory Diseases;Division of Rheumatology;Massachusetts General Hospital;Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital1
