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  • Design, synthesis, and biological evaluation of highly potent small molecule-peptide conjugates as new HIV-1 fusion inhibitors.

Design, synthesis, and biological evaluation of highly potent small molecule-peptide conjugates as new HIV-1 fusion inhibitors.

Journal of medicinal chemistry (2013-03-06)
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
ABSTRACT

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-βAla-P26 and Noc-βAla-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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Proteinase K from Tritirachium album, buffered aqueous glycerol solution, for molecular biology, ≥800 units/mL
Sigma-Aldrich
Proteinase K from Tritirachium album, lyophilized powder, ≥30 units/mg protein
Sigma-Aldrich
Proteinase K from Tritirachium album, ≥500 units/mL, buffered aqueous glycerol solution
Sigma-Aldrich
Proteinase K from Tritirachium album, ≥3.0 unit/mg solid, lyophilized powder
Sigma-Aldrich
Proteinase K from Tritirachium album, lyophilized powder, BioUltra, ≥30 units/mg protein, for molecular biology