Exceptional potency and structural basis of a T1249-derived lipopeptide fusion inhibitor against HIV-1, HIV-2, and simian immunodeficiency virus
Exceptional potency and structural basis of a T1249-derived lipopeptide fusion inhibitor against HIV-1, HIV-2, and simian immunodeficiency virus
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DOI：
10.1074/jbc.ra118.001729
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发表时间：
2018-02
期刊：
影响因子：
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通讯作者：
Yuanmei Zhu;Xiujuan Zhang;Xiaohui Ding;Hui-hui Chong;S. Cui;Jinsheng He;Xinquan Wang;Yuxian He
中科院分区：
文献类型：
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作者：
Yuanmei Zhu;Xiujuan Zhang;Xiaohui Ding;Hui-hui Chong;S. Cui;Jinsheng He;Xinquan Wang;Yuxian He
恩富韦肽（Enfuvirtide, T20）是目前唯一被批准用于临床的病毒融合抑制剂，但其抗hiv活性相对较弱，容易产生耐药。继T20之后，T1249被设计为一种由来自HIV-1、HIV-2和猴免疫缺陷病毒（SIV）的氨基酸序列组成的39聚肽；然而，由于配方困难，其开发一直暂停。我们最近开发了一种基于t20的脂肽（LP-40），其药物性能大大改善。在这里，我们通过用脂肪酸取代其c端富含色氨酸的序列，生成了一个基于t1249的脂肽，称为LP-46。与T20、T1249和LP-40相比，截断的LP-46 （31-mer）抑制大量HIV-1亚型的活性显著增加，IC50值接近低皮摩尔浓度。此外，LP-46对HIV-2、SIV和t20耐药变体具有非常强的抑制作用，并与LP-40表现出明显的协同效应。此外，我们发现LP-46具有更高的螺旋稳定性和与靶位点的结合亲和力。LP-46与靶代物复合物的晶体结构揭示了其作用机制的关键结合基序。有趣的是，我们发现LP-46中引入的口袋结合域并没有像预期的那样与gp41口袋相互作用；相反，它采用了类似LP-40的模式。因此，我们的研究为开发新的抗hiv药物提供了一种特别有效和广泛的融合抑制剂，也可以作为探索病毒融合和抑制机制的工具。
Enfuvirtide (T20) is the only viral fusion inhibitor approved for clinical use, but it has relatively weak anti-HIV activity and easily induces drug resistance. In succession to T20, T1249 has been designed as a 39-mer peptide composed of amino acid sequences derived from HIV-1, HIV-2, and simian immunodeficiency virus (SIV); however, its development has been suspended due to formulation difficulties. We recently developed a T20-based lipopeptide (LP-40) showing greatly improved pharmaceutical properties. Here, we generated a T1249-based lipopeptide, termed LP-46, by replacing its C-terminal tryptophan-rich sequence with fatty acid. As compared with T20, T1249, and LP-40, the truncated LP-46 (31-mer) had dramatically increased activities in inhibiting a large panel of HIV-1 subtypes, with IC50 values approaching low picomolar concentrations. Also, LP-46 was an exceptionally potent inhibitor against HIV-2, SIV, and T20-resistant variants, and it displayed obvious synergistic effects with LP-40. Furthermore, we showed that LP-46 had increased helical stability and binding affinity with the target site. The crystal structure of LP-46 in complex with a target surrogate revealed its critical binding motifs underlying the mechanism of action. Interestingly, it was found that the introduced pocket-binding domain in LP-46 did not interact with the gp41 pocket as expected; instead, it adopted a mode similar to that of LP-40. Therefore, our studies have provided an exceptionally potent and broad fusion inhibitor for developing new anti-HIV drugs, which can also serve as a tool to exploit the mechanisms of viral fusion and inhibition.