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

Authors: Wang, Chao; Shi, Weiguo; Cai, Lifeng; Lu, Lu; Wang, Qian; Zhang, Tianhong; Li, Jinglai; Zhang, Zhenqing; Wang, Kun; Xu, Liang; Jiang, Xifeng; Jiang, Shibo; Liu, Keliang; Journal of Medicinal Chemistry; (2013); 10.1021/jm3018964

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-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 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-cell fusion, but the conjugates properly generated a strong synergistic effect. Among them, conjugates Aoc-?Ala-P26 and Noc-?Ala-P26 exhibited a low nanomolar IC50 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.