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首页> 外文期刊>Journal of Medicinal Chemistry >Design, synthesis, and biological evaluation of highly potent small molecule-peptide conjugates as new HIV-1 fusion inhibitors
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Design, synthesis, and biological evaluation of highly potent small molecule-peptide conjugates as new HIV-1 fusion inhibitors

机译：设计，合成和生物学评估作为新型HIV-1融合抑制剂的高效小分子-肽共轭物

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摘要

The small molecule fusion inhibitors N-(4-carboxy-3-hydroxyphenyl)-2,5- dimethylpyrrole (NB-2) and N-(3-carboxy-4-hydroxyphenyl)-2,5-dimethylpyrrole (A_(12)) target a hydrophobic pocket of HIV-1 gp41 and have moderate anti-HIV-1 activity. In this paper, we report the design, synthesis, and structure-activity relationship of a group of hybrid molecules in which the pocket-binding domain segment of the C34 peptide was replaced with NB-2 and A_(12) derivatives. In addition, the synergistic effect between the small molecule and peptide moieties was analyzed, and lead compounds with a novel scaffold were discovered. We found that either the nonpeptide or peptide part alone showed weak activity against HIV-1-mediated cell-cell fusion, but the conjugates properly generated a strong synergistic effect. Among them, conjugates Aoc-βAla-P26 and Noc-βAla-P26 exhibited a low nanomolar IC_(50) in the cell-cell fusion assay and effectively inhibited T20-sensitive and -resistant HIV-1 strains. Furthermore, the new molecules exhibited better stability against proteinase K digestion than T20 and C34.
机译：小分子融合抑制剂N-（4-羧基-3-羟基苯基）-2,5-二甲基吡咯（NB-2）和N-（3-羧基-4-羟基苯基）-2,5-二甲基吡咯（A_（12） ）靶向HIV-1 gp41的疏水口袋，并具有中等的抗HIV-1活性。在本文中，我们报告了一组杂合分子的设计，合成和构效关系，其中C34肽的口袋结合结构域区段被NB-2和A_（12）衍生物取代。此外，分析了小分子和肽部分之间的协同作用，并发现了具有新型支架的先导化合物。我们发现单独的非肽或肽部分对HIV-1介导的细胞-细胞融合均显示弱的活性，但结合物正确地产生了强大的协同作用。其中，缀合物Aoc-βAla-P26和Noc-βAla-P26在细胞-细胞融合测定中显示出低纳摩尔IC_（50），并有效抑制了T20敏感和耐药HIV-1菌株。此外，新分子对蛋白酶K的消化表现出比T20和C34更好的稳定性。

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