title: Gold manno-glyconanoparticles: multivalent systems to block HIV-1 gp120 binding to the lectin DC-SIGN.
abstract: The HIV envelope glycoprotein gp120 takes advantage of the high-mannose clusters on its surface to target the C-type lectin dendritic cell-specific intracellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) 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 (manno-GNPs) presenting truncated (oligo)mannosides of the high-mannose undecasaccharide Man(9)GlcNAc(2) 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 manno-GNPs have been performed to study their inhibition potency towards DC-SIGN binding to gp120. The tested manno-GNPs completely inhibit the binding from the micro- to the nanomolar range, while the corresponding monovalent mannosides require millimolar concentrations. manno-GNPs containing the disaccharide Manalpha1-2Manalpha are the best inhibitors, showing more than 20 000-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.
authors.affiliation: Laboratory of GlycoNanotechnology, Biofunctional Nanomaterial Unit, CIC biomaGUNE and CIBER-BBN, Parque Tecnológico, San Sebastián, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Martínez-Avila
authors.forename: Karolin
authors.initials: K
authors.lastname: Hijazi
authors.forename: Marco
authors.initials: M
authors.lastname: Marradi
authors.forename: Caroline
authors.initials: C
authors.lastname: Clavel
authors.forename: Colin
authors.initials: C
authors.lastname: Campion
authors.forename: Charles
authors.initials: C
authors.lastname: Kelly
authors.forename: Soledad
authors.initials: S
authors.lastname: Penadés
mesh_terms: D015815:Cell Adhesion Molecules / Q000378:metabolism*; D006046:Gold / Q000737:chemistry*; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D008362:Mannosides / Q000737:chemistry*; D053768:Metal Nanoparticles / Q000737:chemistry*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D006046:Gold; D015699:HIV Envelope Protein gp120; D037181:Lectins, C-Type; D008362:Mannosides; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin