Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 6, Pages 2527-2539Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm3018964
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Funding
- National Science Foundation of China [81072581, 81273560]
- National Science and Technology Major Project of China grant [2012ZX09301003]
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The small molecule fusion inhibitors N-(4-carboxy-3-hydroxyphenyl)-2,5-dimethylpyrrole (NB-2) and N-(3-carboxy-4-hydroxyphenyl)-2,S-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-beta Ala-P26 and Noc-beta 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.
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