Host sphingolipid biosynthesis as a target for hepatitis C virus therapy
Host sphingolipid biosynthesis as a target for hepatitis C virus therapy
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DOI：
10.1038/nchembio742
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发表时间：
2005-11-01
影响因子：
14.8
通讯作者：
Sudoh, M
中科院分区：
文献类型：
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作者：
Sakamoto, H;Okamoto, K;Sudoh, M
据估计，全世界有1.7亿人感染丙型肝炎病毒（HCV），这是慢性肝病的一个严重原因。目前用于治疗HCV感染的基于干扰素的疗法具有不令人满意的治愈率（1，2），并且需要开发更有效的药物。在HCV感染的早期阶段，不同的宿主基因受到不同的调节（3），并且抑制宿主蛋白质可能提供治疗HCV感染的治疗策略。使用HCV亚基因组复制子细胞培养系统，我们从真菌次级代谢产物中鉴定出一种亲脂性长链碱基化合物NA 255（1），一种以前未知的小分子HCV复制抑制剂。NA255阻止鞘脂（主要脂筏组分）的从头合成，从而抑制丝氨酸棕榈酰转移酶，并且它破坏脂筏上HCV非结构（NS）病毒蛋白之间的缔合。此外，我们发现NS5B蛋白在其分子结构中具有鞘脂结合基序，并且该结构域能够直接与鞘磷脂相互作用。因此，NA255是一种新的抗HCV复制抑制剂，其靶向宿主脂筏，这表明抑制鞘脂代谢可能为治疗HCV感染提供新的治疗策略。
An estimated 170 million individuals worldwide are infected with hepatitis C virus (HCV), a serious cause of chronic liver disease. Current interferon-based therapy for treating HCV infection has an unsatisfactory cure rate(1,2), and the development of more efficient drugs is needed. During the early stages of HCV infections, various host genes are differentially regulated(3), and it is possible that inhibition of host proteins affords a therapeutic strategy for treatment of HCV infection. Using an HCV subgenomic replicon cell culture system, here we have identified, from a secondary fungal metabolite, a lipophilic long-chain base compound, NA255 ( 1), a previously unknown small-molecule HCV replication inhibitor. NA255 prevents the de novo synthesis of sphingolipids, major lipid raft components, thereby inhibiting serine palmitoyltransferase, and it disrupts the association among HCV nonstructural (NS) viral proteins on the lipid rafts. Furthermore, we found that NS5B protein has a sphingolipid-binding motif in its molecular structure and that the domain was able to directly interact with sphingomyelin. Thus, NA255 is a new anti-HCV replication inhibitor that targets host lipid rafts, suggesting that inhibition of sphingolipid metabolism may provide a new therapeutic strategy for treatment of HCV infection.