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J Med Chem. 2014 Sep 11;57(17):7342-54. doi: 10.1021/jm500763m. Epub 2014 Aug 26.

Conjugation of a nonspecific antiviral sapogenin with a specific HIV fusion inhibitor: a promising strategy for discovering new antiviral therapeutics.

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Beijing Institute of Pharmacology & Toxicology , 27 Tai-Ping Road, Beijing 100850, China.


Triterpene saponins are a major group of active components in natural products with nonspecific antiviral activities, while T20 peptide (enfuvirtide), which contains a helix zone-binding domain (HBD), is a gp41-specific HIV-1 fusion inhibitor. In this paper, we report the design, synthesis, and structure-activity relationship (SAR) of a group of hybrid molecules in which bioactive triterpene sapogenins were covalently attached to the HBD-containing peptides via click chemistry. We found that either the triterpenes or peptide part alone showed weak activity against HIV-1 Env-mediated cell-cell fusion, while the hybrids generated a strong cooperative effect. Among them, P26-BApc exhibited anti-HIV-1 activity against both T20-sensitive and -resistant HIV-1 strains and improved pharmacokinetic properties. These results suggest that this scaffold design is a promising strategy for developing new HIV-1 fusion inhibitors and possibly novel antiviral therapeutics against other viruses with class I fusion proteins.

[Indexed for MEDLINE]

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