A Serine Palmitoyltransferase Inhibitor Blocks Hepatitis C Virus Replication in Human Hepatocytes
A Serine Palmitoyltransferase Inhibitor Blocks Hepatitis C Virus Replication in Human Hepatocytes
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DOI：
10.1053/j.gastro.2013.06.012
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发表时间：
2013-10-01
期刊：
影响因子：
29.4
通讯作者：
Kohara, Michinori
中科院分区：
文献类型：
--
作者：
Katsume, Asao;Tokunaga, Yuko;Kohara, Michinori
背景与目的：宿主细胞脂筏是丙型肝炎病毒（HCV）复制所必需的支架。丝氨酸棕榈酰转移酶（SPT）产生鞘脂，鞘脂是与HCV非结构蛋白相关的脂筏的重要组成部分。通过SPT抑制剂预防鞘脂的从头合成破坏HCV复制复合物，从而抑制HCV复制。我们研究了SPT抑制剂NA 808在细胞和小鼠中预防HCV复制的能力。方法：在FLR 3 -1复制子细胞中检测NA 808抑制SPT酶活性的能力。我们使用复制子系统来选择在14轮细胞传代后对浓度为50%抑制浓度的4至6倍的NA 808产生抗性的HCV变体。我们评估了NA 808或特拉匹韦抑制HCV基因型1a、1b、2a、3a和4a在人源化肝脏小鼠（移植人肝细胞）中复制的能力。静脉注射NA 808，有或没有聚乙二醇化干扰素α-2a和HCV聚合酶和/或蛋白酶抑制剂。结果：NA 808通过非竞争性抑制SPT阻止HCV复制;未发生耐药突变。NA 808可以阻止在人源化肝脏小鼠中测试的所有HCV基因型的复制。静脉注射NA 808可显著降低小鼠的病毒载量，并与聚乙二醇化干扰素α-2a和HCV聚合酶和蛋白酶抑制剂具有协同作用。结论：SPT抑制剂NA 808可防止HCV基因型1a、1b、2a、3a和4a在培养的肝细胞和人源化肝脏小鼠中复制。它可能被开发用于治疗HCV感染或与聚乙二醇干扰素α-2a或HCV聚合酶或蛋白酶抑制剂联合使用。
BACKGROUND & AIMS: Host cell lipid rafts form a scaffold required for replication of hepatitis C virus (HCV). Serine palmitoyltransferases (SPTs) produce sphingolipids, which are essential components of the lipid rafts that associate with HCV nonstructural proteins. Prevention of the de novo synthesis of sphingolipids by an SPT inhibitor disrupts the HCV replication complex and thereby inhibits HCV replication. We investigated the ability of the SPT inhibitor NA808 to prevent HCV replication in cells and mice. METHODS: We tested the ability of NA808 to inhibit SPT's enzymatic activity in FLR3-1 replicon cells. We used a replicon system to select for HCV variants that became resistant to NA808 at concentrations 4- to 6-fold the 50% inhibitory concentration, after 14 rounds of cell passage. We assessed the ability of NA808 or telaprevir to inhibit replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in mice with humanized livers (transplanted with human hepatocytes). NA808 was injected intravenously, with or without pegylated interferon alfa-2a and HCV polymerase and/or protease inhibitors. RESULTS: NA808 prevented HCV replication via noncompetitive inhibition of SPT; no resistance mutations developed. NA808 prevented replication of all HCV genotypes tested in mice with humanized livers. Intravenous NA808 significantly reduced viral load in the mice and had synergistic effects with pegylated interferon alfa-2a and HCV polymerase and protease inhibitors. CONCLUSIONS: The SPT inhibitor NA808 prevents replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in cultured hepatocytes and in mice with humanized livers. It might be developed for treatment of HCV infection or used in combination with pegylated interferon alfa-2a or HCV polymerase or protease inhibitors.