Genetically-encoded fragment-based discovery of glycopeptide ligands for DC-SIGN

Bioorg Med Chem. 2018 Oct 15;26(19):5368-5377. doi: 10.1016/j.bmc.2018.08.036. Epub 2018 Aug 28.

Abstract

We have employed genetically-encoded fragment-based discovery to identify novel glycopeptides with affinity for the dendritic cell receptor DC-SIGN. Starting from libraries of 108 mannose-conjugated peptides, we identified glycopeptides that exhibited up to a 650-fold increase in multivalent binding affinity for DC-SIGN, which is also preserved in cells. Monovalently, our most potent glycopeptides have a similar potency to a Man3 oligosaccharide, representing a 15-fold increase in activity compared to mannose. These compounds represent the first examples of glycopeptide ligands that target the CRD of DC-SIGN. The natural framework of glycopeptide conjugates and the simplicity of orthogonal conjugation to make these glycopeptides anticipates a promising future for development of DC-SIGN-targeting moieties.

Keywords: DC-SIGN; Glycopeptides; Peptide phage display.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacteriophage M13 / genetics
  • Bacteriophage M13 / metabolism
  • Cell Adhesion Molecules / chemistry
  • Cell Adhesion Molecules / metabolism*
  • Glycopeptides / chemistry*
  • Glycopeptides / metabolism
  • Horseradish Peroxidase / antagonists & inhibitors
  • Horseradish Peroxidase / metabolism
  • Lectins, C-Type / chemistry
  • Lectins, C-Type / metabolism*
  • Ligands
  • Mannose / chemistry
  • Mannose / metabolism
  • Peptide Library
  • Protein Binding
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / metabolism*

Substances

  • Cell Adhesion Molecules
  • DC-specific ICAM-3 grabbing nonintegrin
  • Glycopeptides
  • Lectins, C-Type
  • Ligands
  • Peptide Library
  • Receptors, Cell Surface
  • Horseradish Peroxidase
  • Mannose