A multivalent inhibitor of the DC-SIGN dependent uptake of HIV-1 and Dengue virus

Norbert Varga, Ieva Sutkeviciute, Renato Ribeiro-Viana, Angela Berzi, Rasika Ramdasi, Anna Daghetti, Gerolamo Vettoretti, Ali Amara, Mario Clerici, Javier Rojo, Franck Fieschi, Anna Bernardi

Research output: Contribution to journalArticlepeer-review

Abstract

DC-SIGN is a C-type lectin receptor on antigen presenting cells (dendritic cells) which has an important role in some viral infection, notably by HIV and Dengue virus (DV). Multivalent presentation of carbohydrates on dendrimeric scaffolds has been shown to inhibit DC-SIGN binding to HIV envelope glycoprotein gp120, thus blocking viral entry. This approach has interesting potential applications for infection prophylaxis. In an effort to develop high affinity inhibitors of DC-SIGN mediated viral entry, we have synthesized a group of glycodendrimers of different valency that bear different carbohydrates or glycomimetic DC-SIGN ligands and have studied their DC-SIGN binding activity and antiviral properties both in an HIV and a Dengue infection model. Surface Plasmon Resonance (SPR) competition studies have demonstrated that the materials obtained bind efficiently to DC-SIGN with IC50s in the μm range, which depend on the nature of the ligand and on the valency of the scaffold. In particular, a hexavalent presentation of the DC-SIGN selective antagonist 4 displayed high potency, as well as improved accessibility and chemical stability relative to previously reported dendrimers. At low μm concentration the material was shown to block both DC-SIGN mediated uptake of DV by Raji cells and HIV trans-infection of T cells.

Original languageEnglish
Pages (from-to)4175-4184
Number of pages10
JournalBiomaterials
Volume35
Issue number13
DOIs
Publication statusPublished - Apr 2014

Keywords

  • DC-SIGN
  • Dengue
  • Glycodendrimers
  • Glycomimetics
  • HIV
  • Nanotechnology

ASJC Scopus subject areas

  • Biomaterials
  • Bioengineering
  • Ceramics and Composites
  • Mechanics of Materials
  • Biophysics
  • Medicine(all)

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