title: Conjugation of a nonspecific antiviral sapogenin with a specific HIV fusion inhibitor: a promising strategy for discovering new antiviral therapeutics.
abstract: 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.
authors.affiliation: Beijing Institute of Pharmacology & Toxicology , 27 Tai-Ping Road, Beijing 100850, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.forename: Heya
authors.initials: H
authors.lastname: Na
authors.forename: Xiangpeng
authors.initials: X
authors.lastname: Li
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Xifeng
authors.initials: X
authors.lastname: Jiang
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Xu
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.forename: Tianhong
authors.initials: T
authors.lastname: Zhang
authors.forename: Jinglai
authors.initials: J
authors.lastname: Li
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Zhang
authors.forename: Baohua
authors.initials: B
authors.lastname: Zheng
authors.forename: Guodong
authors.initials: G
authors.lastname: Liang
authors.forename: Lifeng
authors.initials: L
authors.lastname: Cai
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Keliang
authors.initials: K
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D012502:Sapogenins / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D012502:Sapogenins; D000077560:Enfuvirtide