The effect of amantadine on an ion channel protein from Chikungunya virus
The effect of amantadine on an ion channel protein from Chikungunya virus
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DOI：
10.1371/journal.pntd.0007548
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发表时间：
2019-07-01
影响因子：
3.8
通讯作者：
Banerjee, Manidipa
中科院分区：
文献类型：
--
作者：
Dey, Debajit;Siddiqui, Shumaila Iqbal;Banerjee, Manidipa
甲型流感病毒 M2、丙型肝炎病毒 p7、HIV-1 Vpu 和小核糖核酸病毒 2B 等病毒孔蛋白与宿主膜结合，并形成亲水通道，这对于病毒的进入、复制和流出至关重要。据推测，来自甲病毒的 6K 蛋白是病毒孔蛋白，在子代病毒从宿主细胞膜排出的过程中至关重要，尽管基孔肯雅病毒 (CHIKV) 中的类似物仍然相对未知。结合电生理学、共聚焦和电子显微镜以及分子动力学模拟，我们首次证明 CHIKV 6K 是一种离子通道形成蛋白，主要与内质网 (ER) 膜相关。 6K的离子通道活性可以被金刚烷胺抑制，金刚烷胺是一种针对甲型流感病毒M2蛋白开发的抗病毒药物；该药物的存在可以有效抑制培养细胞的CHIKV感染。我们的研究为 CHIKV 与宿主相互作用期间 6K 的功能提供了重要的机制见解，并表明 6K 是一个潜在的治疗药物靶点，金刚烷胺及其衍生物是进一步开发的有力候选者。作者摘要 基孔肯雅热是一种由节肢动物传播的病毒 CHIKV 引起的严重致残疾病。该病毒最初来自非洲次大陆，现已在世界范围内传播，造成巨大的发病率和经济损失。现有的针对 CHIKV 的治疗主要是对症治疗，因此必须设计出具体的治疗方法。本研究提供了对 6K（CHIKV 离子通道形成蛋白）功能的详细了解。金刚烷胺是一种已知的抗流感病毒的抗病毒药物，它还能抑制细胞培养物中的 CHIKV 复制并显着改变病毒颗粒的形态。这项工作强调了病毒编码的膜相互作用蛋白的功能之间惊人的相似之处，这些蛋白可用于开发广谱抗病毒药物。
Viroporins like influenza A virus M2, hepatitis C virus p7, HIV-1 Vpu and picornavirus 2B associate with host membranes, and create hydrophilic corridors, which are critical for viral entry, replication and egress. The 6K proteins from alphaviruses are conjectured to be viroporins, essential during egress of progeny viruses from host membranes, although the analogue in Chikungunya Virus (CHIKV) remains relatively uncharacterized. Using a combination of electrophysiology, confocal and electron microscopy, and molecular dynamics simulations we show for the first time that CHIKV 6K is an ion channel forming protein that primarily associates with endoplasmic reticulum (ER) membranes. The ion channel activity of 6K can be inhibited by amantadine, an antiviral developed against the M2 protein of Influenza A virus; and CHIKV infection of cultured cells can be effectively inhibited in presence of this drug. Our study provides crucial mechanistic insights into the functionality of 6K during CHIKV-host interaction and suggests that 6K is a potential therapeutic drug target, with amantadine and its derivatives being strong candidates for further development.Author summary Chikungunya fever is a severe crippling illness caused by the arthropod-borne virus CHIKV. Originally from the African subcontinent, the virus has now spread worldwide and is responsible for substantial morbidity and economic loss. The existing treatment against CHIKV is primarily symptomatic, and it is imperative that specific therapeutics be devised. The present study provides detailed insight into the functionality of 6K, an ion channel forming protein of CHIKV. Amantadine, a known antiviral against influenza virus, also inhibits CHIKV replication in cell culture and drastically alters the morphology of virus particles. This work highlights striking parallels among functionalities of virus-encoded membrane-interacting proteins, which may be exploited for developing broad-spectrum antivirals.