STRUCTURAL OPTIMIZATION OF MONO AND MULTIVALENT GLYCOMIMETIC MANNOSE BASED DC-SIGN LIGANDS

HIV infection is pandemic in humans and is responsible for millions of deaths every year. The discovery of new cellular targets that can be used to prevent the infection process represents a new opportunity for developing more effective antiviral drugs. In this work, dendritic cell-specific ICAM-3 grabbing non-integrin (DC-SIGN), a lectin expressed at the surface of immature dendritic cells and involved in the initial stages of HIV infection, is described as a promising therapeutic target. The project is being developed within the European research Network CARMUSYS (http://www.carmusys.iiq.csic.es). Herein we show a synthetic work focused on modifications of a dimannoside mimic previously reported by our laboratory. In the first approach the esters are replaced with two identical amide groups and a small focused library of compounds was prepared. In the second modification, the hydroxyl group in position 6 of the mannose residue is replaced with different substitiuents (i.e. by an amine group.) resulting in a small library of glycomimetics. The activities of the prepared molecules towards both DC-SIGN and Langherin were determined using surface plasmon resonance (SPR) technique. It was found that the majority of prepared ligands and are better and more selective DC-SIGN inhibitors then the parent molecule. Further, synthesis of rigid, water soluble spacers – molecular rods is described which were connected to dendrimeric scaffolds bearing the prepared monovalent ligands mentioned above The prepared multivalent structures were tested by SPR technique. Multivalency showed significant improvement of the DC-SIGN inhibition in comparison with the corresponding monovalent ligands.