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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Targeting therapeutics to an exposed and conserved binding element of the HIV-1 fusion protein.
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Targeting therapeutics to an exposed and conserved binding element of the HIV-1 fusion protein.

机译：将治疗剂靶向HIV-1融合蛋白的暴露且保守的结合元件。

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摘要

There is an urgent need for new drugs that can kill HIV type 1 (HIV-1)-infected cells. HIV-1 glycoprotein Env, which promotes viral membrane fusion through receptor-mediated conformational changes, is an attractive target for such agents because it is expressed on the surface of both virions and infected cells. Unfortunately, conserved binding elements on this protein frequently are buried under a canopy of flexible, glycosylated peptide loops or exposed only transiently during the fusion process. Here, we investigate the exposure of the C-terminal region of the Env ectodomain outside the context of membrane fusion. This binding element is the target of the 5-Helix protein, a designed entry inhibitor that disrupts conformational changes in Env subunit gp41, essential for the fusion process. We show that 5-Helix is capable of interacting with HIV-1 Env in a receptor-independent fashion and that a chimeric 5-HelixPseudomonas exotoxin protein recognizes cells expressing Env from a broad spectrum of HIV-1 strains including primary isolates from clades B, D, E, G, and H. This recombinant toxin selectively kills HIV-1-infected cells and blocks spreading infection while still maintaining potent inhibitory activity against membrane fusion. Our results demonstrate that the C-terminal region of the gp41 ectodomain is an accessible target on HIV-1-infected cells for the development of antiviral therapeutics and neutralizing antibodies.
机译：迫切需要可以杀死感染了HIV 1型（HIV-1）的细胞的新药。 HIV-1糖蛋白Env通过受体介导的构象变化促进病毒膜融合，是此类药物的诱人靶标，因为它在病毒体和感染细胞的表面均表达。不幸的是，该蛋白上保守的结合元件经常被埋在柔性的糖基化肽环的冠层下，或者在融合过程中仅被短暂暴露。在这里，我们调查膜融合环境外的Env胞外域的C端区域的暴露。该结合元件是5-Helix蛋白的靶标，后者是一种设计的进入抑制剂，可破坏Env亚基gp41的构象变化，这对于融合过程至关重要。我们证明了5-Helix能够以独立于受体的方式与HIV-1 Env相互作用，并且嵌合的5-HelixPseudomonas外毒素蛋白能够识别从广泛的HIV-1菌株（包括进化枝B的主要分离株）表达Env的细胞。 D，E，G和H。这种重组毒素选择性杀死HIV-1感染的细胞并阻止传播感染，同时仍保持针对膜融合的有效抑制活性。我们的结果表明，gp41胞外域的C端区域是HIV-1感染细胞上可及的靶标，用于开发抗病毒治疗剂和中和抗体。

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