Structural Insights into the Mechanisms of Action of Short-Peptide HIV-1 Fusion Inhibitors Targeting the Gp41 Pocket.
Structural Insights into the Mechanisms of Action of Short-Peptide HIV-1 Fusion Inhibitors Targeting the Gp41 Pocket.
复制标题
针对 Gp41 口袋的短肽 HIV-1 融合抑制剂作用机制的结构见解
DOI：
10.3389/fcimb.2018.00051
复制
发表时间：
2018
影响因子：
5.7
通讯作者：
He Y
中科院分区：
文献类型：
--
作者：
Zhang X;Zhu Y;Hu H;Zhang S;Wang P;Chong H;He J;Wang X;He Y
HIV-1 gp41的深疏水口袋被认为是一个药物靶点，但靶向该位点的短肽通常缺乏有效的抗病毒活性。通过应用M-T钩结构，我们之前生成了特异性靶向口袋位点的高效短肽融合抑制剂，如MT-SC22EK， HP23L和LP-11。在这里，HP23L和LP-11结合到目标模拟肽N36的晶体结构证明了关键的螺旋内和螺旋间相互作用，特别是验证了钩状构象被很好地采用，而蛋氨酸残基被不易氧化的残基亮氨酸取代，并且额外添加一个谷氨酸显著增强了结合和抑制活性。通过两个突变（E49K和L57R）结合N36的HP23L结构揭示了介导耐药的关键残基和基序，为抑制剂的作用机制提供了新的见解。因此，目前的数据有助于我们了解HIV-1融合抑制剂的构效关系（SAR），并促进新型抗病毒药物的开发。
The deep hydrophobic pocket of HIV-1 gp41 has been considered a drug target, but short-peptides targeting this site usually lack potent antiviral activity. By applying the M-T hook structure, we previously generated highly potent short-peptide fusion inhibitors that specifically targeted the pocket site, such as MT-SC22EK, HP23L, and LP-11. Here, the crystal structures of HP23L and LP-11 bound to the target mimic peptide N36 demonstrated the critical intrahelical and interhelical interactions, especially verifying that the hook-like conformation was finely adopted while the methionine residue was replaced by the oxidation-less prone residue leucine, and that addition of an extra glutamic acid significantly enhanced the binding and inhibitory activities. The structure of HP23L bound to N36 with two mutations (E49K and L57R) revealed the critical residues and motifs mediating drug resistance and provided new insights into the mechanism of action of inhibitors. Therefore, the present data help our understanding for the structure-activity relationship (SAR) of HIV-1 fusion inhibitors and facilitate the development of novel antiviral drugs.