Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein.
Itraconazole inhibits enterovirus replication by targeting the oxysterol-binding protein.
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DOI：
10.1016/j.celrep.2014.12.054
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发表时间：
2015-02-03
期刊：
影响因子：
8.8
通讯作者：
van Kuppeveld FJ
中科院分区：
文献类型：
--
作者：
Strating JR;van der Linden L;Albulescu L;Bigay J;Arita M;Delang L;Leyssen P;van der Schaar HM;Lanke KH;Thibaut HJ;Ulferts R;Drin G;Schlinck N;Wubbolts RW;Sever N;Head SA;Liu JO;Beachy PA;De Matteis MA;Shair MD;Olkkonen VM;Neyts J;van Kuppeveld FJ
伊曲康唑(ITZ)是一种著名的抗真菌药物，也具有抗癌活性。在这项研究中，我们将确定ITZ是肠道病毒(例如脊髓灰质炎病毒、柯萨奇病毒、肠道病毒-71、鼻病毒)的广谱抑制剂。我们证明了ITZ通过靶向OSBP和OSBP相关蛋白4(ORP4)来抑制病毒RNA的复制。OSW-1，一种特异性的OSBP/ORP4拮抗剂，也一贯地抑制肠道病毒的复制。敲除OSBP可抑制病毒复制，而过表达OSBP或ORP4可抵消ITZ和OSW-1的抗病毒作用。ITZ结合OSBP并抑制其功能，即胆固醇和磷脂酰肌醇-4-磷酸在膜之间的穿梭，从而可能扰乱病毒诱导的对于病毒复制细胞器形成至关重要的膜改变。ITZ还抑制丙型肝炎病毒复制，丙型肝炎病毒复制也依赖于OSBP。总之，这些数据暗示OSBP/ORP4是ITZ的分子靶点，并指出OSBP/ORP4介导的脂交换在病毒复制中的关键作用，可以被抗病毒药物靶向。Strating等人。介绍抗真菌药物伊曲康唑作为一种广泛病毒的新型抑制剂，包括脊髓灰质炎病毒和丙型肝炎病毒。伊曲康唑作用于一个新的靶点，氧固醇结合蛋白(OSBP)，这是一种在脂质转移中起关键作用的蛋白质。
Itraconazole (ITZ) is a well-known antifungal agent that also has anticancer activity. In this study, we identify ITZ as a broad-spectrum inhibitor of enteroviruses (e.g., poliovirus, coxsackievirus, enterovirus-71, rhinovirus). We demonstrate that ITZ inhibits viral RNA replication by targeting oxysterol-binding protein (OSBP) and OSBP-related protein 4 (ORP4). Consistently, OSW-1, a specific OSBP/ORP4 antagonist, also inhibits enterovirus replication. Knockdown of OSBP inhibits virus replication, whereas overexpression of OSBP or ORP4 counteracts the antiviral effects of ITZ and OSW-1. ITZ binds OSBP and inhibits its function, i.e., shuttling of cholesterol and phosphatidylinositol-4-phosphate between membranes, thereby likely perturbing the virus-induced membrane alterations essential for viral replication organelle formation. ITZ also inhibits hepatitis C virus replication, which also relies on OSBP. Together, these data implicate OSBP/ORP4 as molecular targets of ITZ and point to an essential role of OSBP/ORP4-mediated lipid exchange in virus replication that can be targeted by antiviral drugs. Strating et al. present the antifungal drug itraconazole as a novel inhibitor of a broad range of viruses, including poliovirus and hepatitis C virus. Itraconazole acted on a novel target, the oxysterol-binding protein (OSBP), a protein that has an essential role in lipid transfer.
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