Gold maftfto-glyconanoparticles: Multivalent systems to block HIV-1 gp120 binding to the lectin DC-SIGN

Abstract

The HIV envelope glycoprotein gp120 takes advantage of the highmannose clusters on its surface to target the C-type lectin dendritic cellspecific intracellular adhesion molecule-3-grabbing non-integrin (DCSIGN) on dendritic cells. Mimicking the cluster presentation of oligomannosides on the virus surface is a strategy for designing carbohydrate-based antiviral agents. Bio-inspired by the cluster presentation of gp120, we have designed and prepared a small library of multivalent water-soluble gold glyconanoparticles (wianno-GNPs) presenting truncated (oligo)mannosides of the high-mannose undecasaccharide Man9GlcNAc2 and have tested them as inhibitors of DC-SIGN binding to gp120. These glyconanoparticles are ligands for DC-SIGN, which also interacts in the early steps of infection with a large number of pathogens through specific recognition of associated glycans. (Oligo)mannosides endowed with different spacers ending in thiol groups, which enable attachment of the glycoconjugates to the gold surface, have been prepared. manno-GNPs with different spacers and variable density of mannose (oligo)saccharides have been obtained and characterized. Surface plasmon resonance (SPR) experiments with selected wianno-GNPs have been performed to study their inhibition potency towards DC-SIGN binding to gp120. The tested wianno-GNPs completely inhibit the binding from the micro- to the nanomolar range, while the corresponding monovalent mannosides require millimolar concentrations. wianno-GNPs containing the disaccharide Manal-2Mana are the best inhibitors, showing more than 20000-fold increased activity (100% inhibition at 115 nM) compared to the corresponding monomeric disaccharide (100% inhibition at 2.2 mM). Furthermore, increasing the density of dimannoside on the gold platform from 50 to 100% does not improve the level of inhibition. © 2009 Wiley-VCH Verlag OmbH & Co. KGaA.