The M-T hook structure increases the potency of HIV-1 fusion inhibitor sifuvirtide and overcomes drug resistance
The M-T hook structure increases the potency of HIV-1 fusion inhibitor sifuvirtide and overcomes drug resistance
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M-T钩结构增加了HIV-1融合抑制剂西夫韦肽的效力并克服了耐药性
DOI：
10.1093/jac/dku183
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发表时间：
2014-10-01
影响因子：
5.2
通讯作者：
He, Yuxian
中科院分区：
文献类型：
--
作者：
Chong, Huihui;Yao, Xue;He, Yuxian
目的：从HIV-1 gp41的c端七肽重复序列（CHR）中提取的肽是有效的融合抑制剂。我们最近证明，CHR肽基抑制剂的口袋结合基序之前独特的M-T钩结构可以大大提高其抗病毒活性。在这项研究中，我们应用M-T钩子结构来优化西夫韦肽（SFT），这是一种有效的chrr衍生抑制剂，目前正在中国进行III期临床试验。方法：将两个M-T钩残基（Met-Thr）掺入西氟virtide的n端，生成MT-SFT肽。采用多种结构和功能方法确定MT-SFT的生物物理性质和抗病毒活性。结果：MT-SFT的高分辨率晶体结构显示出高度保守的M-T挂钩构象。与sifuvirtide相比，MT-SFT在结合n端七肽重复序列、阻断六螺旋束形成和抑制HIV-1 env介导的细胞融合、病毒进入和感染方面表现出显著的改善。重要的是，MT-SFT对西呋韦肽和恩呋韦肽（T20）耐药的HIV-1变体具有完全活性，并且对产生耐药性表现出高度的遗传屏障。结论：我们的研究证实，M-T挂钩结构为设计新型HIV-1融合抑制剂提供了一种通用策略，并为病毒进入和抑制提供了新的见解。
Objectives: Peptides derived from the C-terminal heptad repeat (CHR) of HIV-1 gp41 are potent fusion inhibitors. We have recently demonstrated that the unique M-T hook structure preceding the pocket-binding motif of CHR peptide-based inhibitors can greatly improve their antiviral activity. In this study, we applied the M-T hook structure to optimize sifuvirtide (SFT), a potent CHR-derived inhibitor currently under Phase III clinical trials in China.Methods: The peptide MT-SFT was generated by incorporating two M-T hook residues (Met-Thr) into the N-terminus of sifuvirtide. Multiple structural and functional approaches were used to determine the biophysical properties and antiviral activity of MT-SFT.Results: The high-resolution crystal structure of MT-SFT reveals a highly conserved M-T hook conformation. Compared with sifuvirtide, MT-SFT exhibited a significant improvement in the ability to bind to the N-terminal heptad repeat, to block the formation of the six helix bundle and to inhibit HIV-1 Env-mediated cell fusion, viral entry and infection. Importantly, MT-SFT was fully active against sifuvirtide-and enfuvirtide (T20)-resistant HIV-1 variants and displayed a high genetic barrier to developing drug resistance.Conclusions: Our studies have verified that the M-T hook structure offers a general strategy for designing novel HIV-1 fusion inhibitors and provide new insights into viral entry and inhibition.