Design of HIV Coreceptor Derived Peptides That Inhibit Viral Entry at Submicromolar Concentrations.
Design of HIV Coreceptor Derived Peptides That Inhibit Viral Entry at Submicromolar Concentrations.
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设计以亚微摩尔浓度抑制病毒进入的 HIV 辅助受体衍生肽。
DOI：
10.1021/acs.molpharmaceut.7b00155
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发表时间：
2017
影响因子：
4.9
通讯作者：
Bewley,CaroleA
中科院分区：
文献类型：
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作者：
Bobyk,KostyantynD;Mandadapu,SivakoteswaraR;Lohith,Katheryn;Guzzo,Christina;Bhargava,Abhishek;Lusso,Paolo;Bewley,CaroleA
艾滋病毒/艾滋病继续对全球卫生造成巨大负担。目前的HIV治疗剂包括靶向酶HIV蛋白酶、逆转录酶和整合酶的抑制剂，以及沿着通过阻止膜融合或病毒-辅助受体相互作用阻断HIV感染的初始步骤的病毒进入抑制剂。对于后者，来自HIV辅助受体CCR 5的肽先前显示出适度抑制嗜CCR 5的HIV毒株的进入，其中含有第二胞外环的残基178-191的肽（肽2C）显示出最强的抑制。在这里，我们使用了一种迭代的方法，在显示出对结合HIV包膜重要的位置进行氨基酸扫描，并重组有利的取代以大大提高2C的效力。最有效的候选肽获得中和宽度并抑制使用CXCR 4和CXCR 4/CCR 5的病毒，而不仅仅是CCR 5嗜性菌株。我们发现，在没有毒性的情况下，效力的增加高度依赖于氨基酸的位置和残基类型。使用病毒粒子捕获试验，我们表明，2C和新的肽抑制捕获CD 4结合的HIV-1颗粒的抗体，其表位位于或周围的可变环3（V3）的gp 120。抗体结合数据的分析表明，CCR 5 ECL 2衍生肽和gp 120之间的相互作用定位在V3的基部和茎部周围，而不是尖端。在没有一个高分辨率的gp 120结合到辅助受体CCR 5的结构，这些研究结果可能有助于CCR 5替代品的结构研究，设计的肽模拟物具有更高的效力，或作为功能探针进一步研究HIV-1 gp 120-辅助受体的相互作用。
HIV/AIDS continues to pose an enormous burden on global health. Current HIV therapeutics include inhibitors that target the enzymes HIV protease, reverse transcriptase, and integrase, along with viral entry inhibitors that block the initial steps of HIV infection by preventing membrane fusion or virus–coreceptor interactions. With regard to the latter, peptides derived from the HIV coreceptor CCR5 were previously shown to modestly inhibit entry of CCR5-tropic HIV strains, with a peptide containing residues 178–191 of the second extracellular loop (peptide2C) showing the strongest inhibition. Here we use an iterative approach of amino acid scanning at positions shown to be important for binding the HIV envelope, and recombining favorable substitutions to greatly improve the potency of2C. The most potent candidate peptides gain neutralization breadth and inhibit CXCR4 and CXCR4/CCR5-using viruses, rather than CCR5-tropic strains only. We found that gains in potency in the absence of toxicity were highly dependent on amino acid position and residue type. Using virion capture assays we show that2Cand the new peptides inhibit capture of CD4-bound HIV-1 particles by antibodies whose epitopes are located in or around variable loop 3 (V3) on gp120. Analysis of antibody binding data indicates that interactions between CCR5 ECL2-derived peptides and gp120 are localized around the base and stem of V3 more than the tip. In the absence of a high-resolution structure of gp120 bound to coreceptor CCR5, these findings may facilitate structural studies of CCR5 surrogates, design of peptidomimetics with increased potency, or use as functional probes for further study of HIV-1 gp120–coreceptor interactions.