Cyclopeptides design as blockers against HCV p7 channel in silico
Cyclopeptides design as blockers against HCV p7 channel in silico
复制标题
环肽设计作为 HCV p7 通道阻断剂的计算机模拟
DOI：
10.1080/08927022.2019.1641604
复制
发表时间：
2019-07-12
影响因子：
2.1
通讯作者：
Wang, Jingfang
中科院分区：
文献类型：
--
作者：
Pang, Shichao;Zhao, Rongcheng;Wang, Jingfang
丙型肝炎病毒p7蛋白是一种63个残基的跨膜蛋白，通过寡聚作用形成具有阳离子选择性的离子通道。这种蛋白质对于组装和释放具有感染性的病毒颗粒是必不可少的。结构分析表明，p7六角体通道的瓶颈位于天冬酰胺的圆锥区第9位，孔半径为3.9 ä，质子化后孔半径减小到近3.0 ä。金刚烷胺和BIT225作为变构抑制剂结合在p7通道面脂一侧的疏水口袋中，以闭合构象稳定通道孔。在这里，我们根据丙型肝炎病毒p7蛋白通道瓶颈的化学和物理特性，设计了一系列环肽作为锥体区域的内通道阻滞剂。结果发现，环-4-天冬氨酸以良好的结合亲和力结合在门控残基Ile6和Asn9之间的通道腔中，与圆锥区的疏水口袋完全匹配。与金刚烷胺和BIT225比较，我们认为这些环肽具有潜在的抗丙型肝炎病毒p7蛋白的作用。
ABSTRACT The protein p7 in the hepatitis C virus (HCV) is a 63-residue transmembrane protein that oligomerizes to form an ion channel with cation selectivity. This protein is essential for the assembly and release of infectious viral particles. Structural analysis indicates that the bottleneck of the p7 hexamer channel is located on Asparagines at position 9 in the conical region with a pore radius of 3.9 Å, which is reduced to nearly 3.0 Å upon protonation. Amantadine and BIT225 binds in the hydrophobic pocket on the lipid-facing side of the p7 channel as allosteric inhibitors to stabilise the channel pore in a closed conformation. Here, we designed a series of cyclopeptides as inner channel blockers in the conical region based on chemical and physical characteristics of the channel bottleneck for the HCV p7 protein. As a result, cyclic-4-Asp is found to bind in the channel lumen between the gating residues Ile6 and Asn9 with a favourable binding affinity, perfectly fitting with the hydrophobic pocket in the conical region. Compared with amantadine and BIT225, we believe that the cylcopeptides have potential to be effective inhibitors against HCV p7 protein.