Mechanism of HIV-1 Resistance to Short-Peptide Fusion Inhibitors Targeting the Gp41 Pocket
Mechanism of HIV-1 Resistance to Short-Peptide Fusion Inhibitors Targeting the Gp41 Pocket
复制标题
HIV-1 对针对 Gp41 口袋的短肽融合抑制剂的耐药机制
DOI：
10.1128/jvi.00373-15
复制
发表时间：
2015-06-01
影响因子：
5.4
通讯作者：
He, Yuxian
中科院分区：
文献类型：
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作者：
Su, Yang;Chong, Huihiui;He, Yuxian
HIV-1 gp 41蛋白N三聚体上的深疏水口袋被认为是理想的药物靶点。基于M-T hook结构，我们最近开发了基于短肽的HIV-1融合抑制剂（MTSC 22和HP 23），其主要靶向口袋位点，具有高效的抗病毒活性。在这项研究中，我们重点研究了它们的耐药途径和机制，通过逃避HIV-1突变体对SC22 EK，一个模板肽MTSC 22和HP 23。分别位于gp 41的N-和C-七肽重复区的两个取代E49 K和N126 K被鉴定为赋予对靶向口袋的抑制剂的高抗性以及对恩夫韦肽（T20）和西夫韦肽（SFT）的交叉抗性。SC22 EK诱导的抗性的潜在机制包括以下：（i）抑制剂的结合亲和力显著降低，（ii）病毒六螺旋束的相互作用显著增强，和（iii）病毒Env复合物的功能严重受损。这些结果为研究gp 41的结构与功能关系以及病毒融合抑制剂的构效关系提供了重要信息。恩夫韦肽（Enfuvirtide，T20）是唯一一种临床使用的HIV-1融合抑制剂，但耐药性问题严重限制了其使用，需要新的策略或概念来开发下一代药物。基于M-T钩结构，特异性靶向gp 41口袋位点的短肽HIV-1融合抑制剂表现出高结合和抗病毒活性。在这里，我们研究了HIV-1耐短抑制剂的分子途径，通过选择和定位逃逸突变体。耐药性的关键替代物及其潜在机制已得到很好的表征。这些数据为gp 41及其抑制剂的结构-功能关系提供了重要信息，必将有助于我们未来开发阻断gp 41依赖性融合的新药。
ABSTRACT The deep hydrophobic pocket on the N trimer of HIV-1 gp41 has been considered an ideal drug target. On the basis of the M-T hook structure, we recently developed short-peptide-based HIV-1 fusion inhibitors (MTSC22 and HP23), which mainly target the pocket site and possess highly potent antiviral activity. In this study, we focused on investigating their resistance pathways and mechanisms by escape HIV-1 mutants to SC22EK, a template peptide for MTSC22 and HP23. Two substitutions, E49K and N126K, located, respectively, at the N- and C-heptad repeat regions of gp41, were identified as conferring high resistance to the inhibitors targeting the pocket and cross-resistance to enfuvirtide (T20) and sifuvirtide (SFT). The underlying mechanisms of SC22EK-induced resistance include the following: (i) significantly reduced binding affinity of the inhibitors, (ii) dramatically enhanced interaction of the viral six-helix bundle, and (iii)severely damaged functionality of the viral Env complex. Our data have provided important information for the structure-function relationship of gp41 and the structure-activity relationship of viral fusion inhibitors. IMPORTANCE Enfuvirtide (T20) is the only HIV-1 fusion inhibitor in clinical use, but the problem of resistance significantly limits its use, calling for new strategies or concepts to develop next-generation drugs. On the basis of the M-T hook structure, short-peptide HIV-1 fusion inhibitors specifically targeting the gp41 pocket site exhibit high binding and antiviral activities. Here, we investigated the molecular pathway of HIV-1 resistance to the short inhibitors by selecting and mapping the escape mutants. The key substitutions for resistance and the underlying mechanisms have been finely characterized. The data provide important information for the structure-function relationship of gp41 and its inhibitors and will definitely help our future development of novel drugs that block gp41-dependent fusion.