Design,Synthesis, and Biological Evaluation of Highly Potent Small Molecule–PeptideConjugates as New HIV-1 Fusion Inhibitors.

Thesmall 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 havemoderate anti-HIV-1 activity. In this paper, we report the design,synthesis, and structure–activity relationship of a group ofhybrid molecules in which the pocket-binding domain segment of theC34 peptide was replaced with NB-2 and A12derivatives.In addition, the synergistic effect between the small molecule andpeptide moieties was analyzed, and lead compounds with a novel scaffoldwere discovered. We found that either the nonpeptide or peptide partalone showed weak activity against HIV-1-mediated cell–cellfusion, but the conjugates properly generated a strong synergisticeffect. Among them, conjugates Aoc−βAla–P26 andNoc−βAla–P26 exhibited a low nanomolar IC50in the cell–cell fusion assay and effectively inhibitedT20-sensitive and -resistant HIV-1 strains. Furthermore, the new moleculesexhibited better stability against proteinase K digestion than T20and C34. [ABSTRACT FROM AUTHOR]