SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells
SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells
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DOI：
10.1128/aac.50.3.1013-1020.2006
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发表时间：
2006-03-01
影响因子：
4.9
通讯作者：
Njoroge, FG
中科院分区：
文献类型：
--
作者：
Malcolm, BA;Liu, R;Njoroge, FG
丙型肝炎病毒（HCV）多聚蛋白被病毒NS 3蛋白酶切割释放病毒复制所必需的功能性病毒蛋白。Foy及其同事最近的研究强烈表明，NS 3介导的宿主因子裂解可能消除对α干扰素（IFN-α）的细胞应答（E. Foy，K.利河，巴西-地小桑普特，Y.-- M.卢角L.约翰逊，C.王，P.M.鱼，M。米山，T.藤田S. M. Lemon和M.小盖尔Proc. Natl. Acad. Sci. USA 102：2986-2991，2005和E. Foy，K. Li，C.王河，巴西-地小桑普特，M. Ikeda，S. M. Lemon和M.小盖尔Science 300：1145-1148，2003）。因此，预期NS 3蛋白酶活性的阻断通过直接抑制病毒蛋白产生以及通过恢复宿主对IFN的应答性来抑制HCV复制。使用结构辅助设计，生成了一种酮酰胺抑制剂SCH 503034，其在无细胞酶试验中表现出对NS 3蛋白酶的强效（总抑制常数，14 nM）时间依赖性抑制作用，并在HCV复制子系统中表现出稳健的体外活性（通过免疫荧光和实时PCR分析监测）。将携带复制子的细胞系连续暴露于6倍于90%有效浓度的SCH 503034 15天，导致复制子RNA减少超过4个对数。SCH 503034与IFN联合用药在抑制复制子合成方面比单独使用任一种化合物更有效，支持Foy及其同事的建议，即IFN与蛋白酶抑制剂联合用药可增强疗效。
Cleavage of the hepatitis C virus (HCV) polyprotein by the viral NS3 protease releases functional viral proteins essential for viral replication. Recent studies by Foy and coworkers strongly suggest that NS3-mediated cleavage of host factors may abrogate cellular response to alpha interferon (IFN-alpha) (E. Foy, K. Li, R. Sumpter, Jr., Y.-M. Loo, C. L. Johnson, C. Wang, P. M. Fish, M. Yoneyama, T. Fujita, S. M. Lemon, and M. Gale, Jr., Proc. Natl. Acad. Sci. USA 102:2986-2991, 2005, and E. Foy, K. Li, C. Wang, R. Sumpter, Jr., M. Ikeda, S. M. Lemon, and M. Gale, Jr., Science 300:1145-1148, 2003). Blockage of NS3 protease activity therefore is expected to inhibit HCV replication by both direct suppression of viral protein production as well as by restoring host responsiveness to IFN. Using structure-assisted design, a ketoamide inhibitor, SCH 503034, was generated which demonstrated potent (overall inhibition constant, 14 nM) time-dependent inhibition of the NS3 protease in cell-free enzyme assays as well as robust in vitro activity in the HCV replicon system, as monitored by immunofluorescence and real-time PCR analysis. Continuous exposure of replicon-bearing cell lines to six times the 90% effective concentration of SCH 503034 for 15 days resulted in a greater than 4-log reduction in replicon RNA. The combination of SCH 503034 with IFN was more effective in suppressing replicon synthesis than either compound alone, supporting the suggestion of Foy and coworkers that combinations of IFN with protease inhibitors would lead to enhanced therapeutic efficacy.