Design of a highly potent HIV-1 fusion inhibitor targeting the gp41 pocket
Design of a highly potent HIV-1 fusion inhibitor targeting the gp41 pocket
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针对 gp41 口袋的高效 HIV-1 融合抑制剂的设计
DOI：
10.1097/qad.0000000000000498
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发表时间：
2015-01-02
期刊：
影响因子：
3.8
通讯作者：
He, Yuxian
中科院分区：
文献类型：
--
作者：
Chong, Huihui;Qiu, Zonglin;He, Yuxian
目的：T20 （Enfuvirtide）是一种由gp41的c -末端七肽重复序列（CHR）衍生而来的36位残基肽，是目前临床唯一可用的HIV-1融合抑制剂，但其易诱导耐药，这需要下一代药物的开发。设计：我们最近证明M-T钩结构可以用来设计一个短的CHR肽，专门针对保守的gp41口袋而不是t20抗性位点。我们试图基于MT-SC22EK的构效关系开发更有效的HIV-1融合抑制剂。方法：采用多种生物物理和功能方法测定抑制剂的结构特征、结合亲和力和抗hiv活性。结果：23残基肽HP23在溶液中呈螺旋状三聚体状态，主要包含M-T钩结构和口袋结合序列。HP23具有显著的结合稳定性和抗病毒活性，是M-T钩子修饰和未修饰对照肽的最有效抑制剂。更有希望的是，HP23在抑制多种HIV-1亚型（包括T20和MT-SC22EK耐药HIV-1突变体）方面表现出高度的活性，并且对抗性的发展表现出高度的遗传屏障。结论：我们的研究提供了一种理想的HIV-1融合抑制剂，它特异性地靶向高度保守的gp41口袋，并具有有效的结合和抗病毒活性。此外，HP23可以作为探索HIV-1融合和抑制机制的关键工具。
Objective:T20 (Enfuvirtide), which is a 36-residue peptide derived from the C-terminal heptad repeat (CHR) of gp41, is the only clinically available HIV-1 fusion inhibitor, but it easily induces drug resistance, which calls for next-generation drugs. Design:We recently demonstrated that the M-T hook structure can be used to design a short CHR peptide that specifically targets the conserved gp41 pocket rather than the T20-resistant sites. We attempted to develop more potent HIV-1 fusion inhibitors based on the structure–activity relationship of MT-SC22EK. Methods:Multiple biophysical and functional approaches were performed to determine the structural features, binding affinities and anti-HIV activities of the inhibitors. Results:The 23-residue peptide HP23, which mainly contains the M-T hook structure and pocket-binding sequence, showed a helical and trimeric state in solution. HP23 had dramatically improved binding stability and antiviral activity, and it was the most potent inhibitor of the M-T hook-modified and unmodified control peptides. More promisingly, HP23 was highly active in the inhibition of diverse HIV-1 subtypes, including T20 and MT-SC22EK resistant HIV-1 mutants, and it exhibited a high genetic barrier to the development of resistance. Conclusion:Our studies delivered an ideal HIV-1 fusion inhibitor that specifically targeted the highly conserved gp41 pocket and possessed potent binding and antiviral activity. Furthermore, HP23 can serve as a critical tool to explore the mechanisms of HIV-1 fusion and inhibition.