Pseudosaccharide functionalized dendrimers as potent inhibitors of DC-SIGN dependent Ebola pseudotyped viral infection

Bioconjug Chem. 2011 Jul 20;22(7):1354-65. doi: 10.1021/bc2000403. Epub 2011 Jun 20.

Abstract

The development of compounds with strong affinity for the receptor DC-SIGN is a topic of remarkable interest due to the role that this lectin plays in several pathogen infection processes and in the modulation of the immune response. DC-SIGN recognizes mannosylated and fucosylated oligosaccharides in a multivalent manner. Therefore, multivalent carbohydrate systems are required to interact in an efficient manner with this receptor and compete with the natural ligands. We have previously demonstrated that linear pseudodi- and pseudotrisaccharides are adequate ligands for DC-SIGN. In this work, we show that multivalent presentations of these glycomimetics based on polyester dendrons and dendrimers lead to very potent inhibitors (in the nanomolar range) of cell infection by Ebola pseudotyped viral particles by blocking DC-SIGN receptor. Furthermore, SPR model experiments confirm that the described multivalent glycomimetic compounds compete in a very efficient manner with polymannosylated ligands for binding to DC-SIGN.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology*
  • Carbohydrates / chemistry*
  • Carbohydrates / pharmacology*
  • Cell Adhesion Molecules / antagonists & inhibitors*
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Cell Line
  • Dendrimers / chemistry*
  • Dendrimers / pharmacology*
  • Ebolavirus / drug effects
  • Gene Expression
  • Hemorrhagic Fever, Ebola / drug therapy*
  • Humans
  • Jurkat Cells
  • Lectins, C-Type / antagonists & inhibitors*
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism
  • Protein Binding
  • Receptors, Cell Surface / antagonists & inhibitors*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Surface Plasmon Resonance

Substances

  • Antiviral Agents
  • Carbohydrates
  • Cell Adhesion Molecules
  • DC-specific ICAM-3 grabbing nonintegrin
  • Dendrimers
  • Lectins, C-Type
  • Receptors, Cell Surface