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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Enfuvirtide
  • HIV Envelope Protein gp41 / chemistry
  • HIV Envelope Protein gp41 / genetics
  • HIV Envelope Protein gp41 / pharmacology*
  • HIV Fusion Inhibitors / chemistry
  • HIV Fusion Inhibitors / pharmacology*
  • HIV-1 / drug effects
  • Humans
  • Models, Chemical
  • Models, Molecular
  • Molecular Sequence Data
  • Molecular Structure
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / pharmacology*
  • Protein Structure, Secondary
  • Sapogenins / chemistry
  • Sapogenins / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • HIV Envelope Protein gp41
  • HIV Fusion Inhibitors
  • Peptide Fragments
  • Sapogenins
  • Enfuvirtide