Synthesis of novel mannoside glycolipid conjugates for inhibition of HIV-1 trans-infection.
Fiche publication
Date publication
septembre 2012
Auteurs
Membres identifiés du Cancéropôle Est :
Dr WAGNER Alain, Dr MUELLER Christopher
Tous les auteurs :
Dehuyser L, Schaeffer E, Chaloin O, Mueller CG, Baati R, Wagner A
Lien Pubmed
Résumé
Mannose-binding lectins, such as dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN), are expressed at the surface of human dendritic cells (DCs) that capture and transmit human immunodeficiency virus type-1 (HIV-1) to CD4(+) cells. With the goal of reducing viral trans-infection by targeting DC-SIGN, we have designed a new class of mannoside glycolipid conjugates. We report the synthesis of amphiphiles composed of a mannose head, a hydrophilic linker essential for solubility in aqueous media, and a lipid chain of variable length. These conjugates presented unusual properties based on a cooperation between the mannoside head and the lipid chain, which enhanced the affinity and decreased the need for multivalency. With an optimal lipid length, they exhibited strong binding affinity for DC-SIGN (K(d) in the micromolar range) as assessed by surface plasmon resonance. The most active molecules were branched trimannoside conjugates, able to inhibit the interaction of the HIV-1 envelope with DCs, and to drastically reduce trans-infection of HIV-1 mediated by DCs (IC(50s) in the low micromolar range). This new class of compounds may be of potential use for prevention of HIV-1 dissemination, and also of infection by other DC-SIGN-binding human pathogens.
Référence
Bioconjug Chem. 2012 Sep 19;23(9):1731-9