Chinese Academy of Medical Sciences, 9 Dong Dan San Tiao, Beijing 100730, China.
FASEB J. 2013 Mar;27(3):1203-13. doi: 10.1096/fj.12-222547. Epub 2012 Dec 11.
Peptides derived from the C-terminal heptad repeat (C peptides) of HIV-1 gp41 are potent inhibitors against virus entry. However, development of a short C peptide possessing high anti-HIV potency is considered a daunting challenge. We recently discovered that the residues Met626 and Thr627 preceding the pocket-binding domain of the C peptide adopt a unique M-T hook structure that is crucial for the design of HIV-1 fusion inhibitors. In this study, we first presented a proof-of-concept prototype that the M-T hook residues can dramatically improve the antiviral activity and thermostability of a short C peptide. We then generated a 24-mer peptide termed MT-SC22EK by incorporating the M-T hook structure to the N terminus of the poorly active short C peptide SC22EK. Amazingly, MT-SC22EK inhibited HIV-1-mediated cell fusion and infection at a level comparable to C34, T1249, SC29EK, and sifuvirtide, and it was highly active against diverse HIV-1 subtypes and variants, including those T20 (enfuvirtide) and SC29EK-resistant viruses. The high-resolution crystal structure of MT-SC22EK reveals the N-terminal M-T hook conformation folded by incorporated Met626 and Thr627 and identifies the C-terminal boundary critical for the anti-HIV activity. Collectively, our studies provide new insights into the mechanisms of HIV-1 fusion and its inhibition.
HIV-1 gp41 的 C 端七肽重复（C 肽）衍生的肽是有效的病毒进入抑制剂。然而，开发具有高抗 HIV 活性的短 C 肽被认为是一项艰巨的挑战。我们最近发现，C 肽口袋结合域前的残基 Met626 和 Thr627 采用独特的 M-T 钩结构，这对于 HIV-1 融合抑制剂的设计至关重要。在这项研究中，我们首先提出了一个概念验证原型，即 M-T 钩残基可以显著提高短 C 肽的抗病毒活性和热稳定性。然后，我们通过将 M-T 钩结构整合到活性较差的短 C 肽 SC22EK 的 N 端，生成了一个 24 肽，称为 MT-SC22EK。令人惊讶的是，MT-SC22EK 以与 C34、T1249、SC29EK 和 sifuvirtide 相当的水平抑制 HIV-1 介导的细胞融合和感染，并且对多种 HIV-1 亚型和变体具有高度活性，包括 T20（恩夫韦肽）和 SC29EK 耐药病毒。MT-SC22EK 的高分辨率晶体结构揭示了由整合的 Met626 和 Thr627 折叠的 N 端 M-T 钩构象，并确定了对抗 HIV 活性至关重要的 C 端边界。总之，我们的研究为 HIV-1 融合及其抑制的机制提供了新的见解。
