Uncovering oxysterol-binding protein (OSBP) as a target of the anti-enteroviral compound TTP-8307
Uncovering oxysterol-binding protein (OSBP) as a target of the anti-enteroviral compound TTP-8307
复制标题
DOI：
10.1016/j.antiviral.2017.01.008
复制
发表时间：
2017-04-01
影响因子：
7.6
通讯作者：
Strating, Jeroen R. P. M.
中科院分区：
文献类型：
--
作者：
Albulescu, Lucian;Bigay, Joelle;Strating, Jeroen R. P. M.
正链RNA病毒的小核糖核酸病毒科的肠道病毒属（例如脊髓灰质炎病毒、柯萨奇病毒、鼻病毒）包括与一系列急性和慢性疾病相关的许多重要病原体，对于这些疾病没有批准的抗病毒疗法可用。靶向高度保守的生命周期中的一个步骤为开发肠病毒感染的广谱抑制剂提供了有吸引力的策略。目前作为开发抗病毒药物的目标而探索的一个步骤是形成复制细胞器，其支持病毒基因组的复制。为了建立复制细胞器，肠道病毒重新连接细胞机器并劫持脂质稳态途径。例如，肠道病毒利用PI 4KIIII β-PI 4P-OSBP途径将胆固醇引导至复制细胞器。在这里，我们发现TTP-8307，一种已知的肠道病毒复制抑制剂，通过PI 4KIII-PI 4P-OSBP途径直接抑制OSBP活性。然而，尽管1 TP-8307与已建立的OSBP抑制剂（伊曲康唑和OSW-1）具有共同的机制，但我们确定了这些化合物之间的许多显著差异。TTP-8307的抗病毒活性延伸到需要OSBP的其他病毒，即小核糖核酸病毒脑心肌炎病毒和黄病毒丙型肝炎病毒。(C)2017作者由Elsevier B. V.发布。这是CC BY许可下的开放获取文章
The genus Enterovirus (e.g. poliovirus, coxsackievirus, rhinovirus) of the Picornaviridae family of positive strand RNA viruses includes many important pathogens linked to a range of acute and chronic diseases for which no approved antiviral therapy is available. Targeting a step in the life cycle that is highly conserved provides an attractive strategy for developing broad-range inhibitors of enterovirus infection. A step that is currently explored as a target for the development of antivirals is the formation of replication organelles, which support replication of the viral genome. To build replication organelles, enteroviruses rewire cellular machinery and hijack lipid homeostasis pathways. For example, enteroviruses exploit the PI4KIIII beta-PI4P-OSBP pathway to direct cholesterol to replication organelles. Here, we uncover that TTP-8307, a known enterovirus replication inhibitor, acts through the PI4KIIII-PI4P-OSBP pathway by directly inhibiting OSBP activity. However, despite a shared mechanism of 1TP-8307 with established OSBP inhibitors (itraconazole and OSW-1), we identify a number of notable differences between these compounds. The antiviral activity of TTP-8307 extends to other viruses that require OSBP, namely the picornavirus encephalomyocarditis virus and the flavivirus hepatitis C virus. (C) 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license