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Triterpenesaponins are a major group of active components in natural productswith nonspecific antiviral activities, while T20 peptide (enfuvirtide),which contains a helix zone-binding domain (HBD), is a gp41-specificHIV-1 fusion inhibitor. In this paper, we report the design, synthesis,and structure–activity relationship (SAR) of a group of hybridmolecules in which bioactive triterpene sapogenins were covalentlyattached to the HBD-containing peptides via click chemistry. We foundthat either the triterpenes or peptide part alone showed weak activityagainst HIV-1 Env-mediated cell–cell fusion, while the hybridsgenerated a strong cooperative effect. Among them, P26–BApcexhibited anti-HIV-1 activity against both T20-sensitive and -resistantHIV-1 strains and improved pharmacokinetic properties. These resultssuggest that this scaffold design is a promising strategy for developingnew HIV-1 fusion inhibitors and possibly novel antiviral therapeuticsagainst other viruses with class I fusion proteins. [ABSTRACT FROM AUTHOR]

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]