Design, Synthesis, and Biological Evaluation of Highly Potent Small Molecule鈥揚eptide Conjugates as New HIV-1 Fusion Inhibitors

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• 作者：Chao Wang ; Weiguo Shi ; Lifeng Cai ; Lu Lu ; Qian Wang ; Tianhong Zhang ; Jinglai Li ; Zhenqing Zhang ; Kun Wang ; Liang Xu ; Xifeng Jiang ; Shibo Jiang ; Keliang Liu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2527-2539
• 全文大小：555K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

The small molecule fusion inhibitors N-(4-carboxy-3-hydroxyphenyl)-2,5-dimethylpyrrole (NB-2) and N-(3-carboxy-4-hydroxyphenyl)-2,5-dimethylpyrrole (A₁₂) 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鈥揳ctivity relationship of a group of hybrid molecules in which the pocket-binding domain segment of the C34 peptide was replaced with NB-2 and A₁₂ 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鈥揷ell fusion, but the conjugates properly generated a strong synergistic effect. Among them, conjugates Aoc鈭捨睞la鈥揚26 and Noc鈭捨睞la鈥揚26 exhibited a low nanomolar IC₅₀ in the cell鈥揷ell 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.