a novel small molecule inhibitor of hepatitis c virus entry一种新型小分子抑制剂丙型肝炎病毒的条目.pdfVIP

A Novel Small Molecule Inhibitor of Hepatitis C Virus Entry Carl J. Baldick*, Michael J. Wichroski, Annapurna Pendri, Ann W. Walsh, Jie Fang, Charles E. Mazzucco, Kevin A. Pokornowski, Ronald E. Rose, Betsy J. Eggers, Mayla Hsu¤, Weixu Zhai, Guangzhi Zhai, Samuel W. Gerritz, Michael A. Poss, Nicholas A. Meanwell, Mark I. Cockett, Daniel J. Tenney Bristol-Myers Squibb, Research and Development, Wallingford, Connecticut, United States of America Abstract Small molecule inhibitors of hepatitis C virus (HCV) are being developed to complement or replace treatments with pegylated interferons and ribavirin, which have poor response rates and significant side effects. Resistance to these inhibitors emerges rapidly in the clinic, suggesting that successful therapy will involve combination therapy with multiple inhibitors of different targets. The entry process of HCV into hepatocytes represents another series of potential targets for therapeutic intervention, involving viral structural proteins that have not been extensively explored due to experimental limitations. To discover HCV entry inhibitors, we utilized HCV pseudoparticles (HCVpp) incorporating E1-E2 envelope proteins from a genotype 1b clinical isolate. Screening of a small molecule library identified a potent HCV-specific triazine inhibitor, EI-1. A series of HCVpp with E1-E2 sequences from various HCV isolates was used to show activity against all genotype 1a and 1b HCVpp tested, with median EC50 values of 0.134 and 0.027 mM, respectively. Time-of-addition experiments demonstrated a block in HCVpp entry, downstream of initial attachment to the cell surface, and prior to or concomitant with bafilomycin inhibition of endosomal acidification. EI-1 was equally active against cell-culture adapted HCV (HCVcc), blocking bot