Conjugation of a Nonspecific Antiviral Sapogenin with a Specific HIV Fusion Inhibitor: A Promising Strategy for Discovering New Antiviral Therapeutics

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• 作者：Chao Wang ; Lu Lu ; Heya Na ; Xiangpeng Li ; Qian Wang ; Xifeng Jiang ; Xiaoyu Xu ; Fei Yu ; Tianhong Zhang ; Jinglai Li ; Zhenqing Zhang ; Baohua Zheng ; Guodong Liang ; Lifeng Cai ; Shibo Jiang ; Keliang Liu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：September 11, 2014
• 年：2014
• 卷：57
• 期：17
• 页码：7342-7354
• 全文大小：572K
• ISSN：1520-4804

文摘

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鈥揳ctivity 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鈥揷ell fusion, while the hybrids generated a strong cooperative effect. Among them, P26鈥揃Apc 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.