title: Docking, synthesis, and NMR studies of mannosyl trisaccharide ligands for DC-SIGN lectin.
abstract: DC-SIGN, a lectin, which presents at the surface of immature dendritic cells, constitutes nowadays a promising target for the design of new antiviral drugs. This lectin recognizes highly glycosylated proteins present at the surface of several pathogens such as HIV, Ebola virus, Candida albicans, Mycobacterium tuberculosis, etc. Understanding the binding mode of this lectin is a topic of tremendous interest and will permit a rational design of new and more selective ligands. Here, we present computational and experimental tools to study the interaction of di- and trisaccharides with DC-SIGN. Docking analysis of complexes involving mannosyl di- and trisaccharides and the carbohydrate recognition domain (CRD) of DC-SIGN have been performed. Trisaccharides Manalpha1,2[Manalpha1,6]Man 1 and Manalpha1,3[Manalpha1,6]Man 2 were synthesized from an orthogonally protected mannose as a common intermediate. Using these ligands and the soluble extracellular domain (ECD) of DC-SIGN, NMR experiments based on STD and transfer-NOE were performed providing additional information. Conformational analysis of the mannosyl ligands in the free and bound states was done. These studies have demonstrated that terminal mannoses at positions 2 or 3 in the trisaccharides are the most important moiety and present the strongest contact with the binding site of the lectin. Multiple binding modes could be proposed and therefore should be considered in the design of new ligands.
authors.affiliation: Grupo de Carbohidratos, Instituto de Investigaciones Químicas, CSIC, Universidad de Sevilla, Américo Vespucio 49, Seville, Spain.
authors.forename: José J
authors.initials: JJ
authors.lastname: Reina
authors.forename: Irene
authors.initials: I
authors.lastname: Díaz
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Nieto
authors.forename: Nuria E
authors.initials: NE
authors.lastname: Campillo
authors.forename: Juan A
authors.initials: JA
authors.lastname: Páez
authors.forename: Georges
authors.initials: G
authors.lastname: Tabarani
authors.forename: Franck
authors.initials: F
authors.lastname: Fieschi
authors.forename: Javier
authors.initials: J
authors.lastname: Rojo
mesh_terms: D001667:Binding, Competitive; D002236:Carbohydrate Conformation; D015815:Cell Adhesion Molecules / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D037181:Lectins, C-Type / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008358:Mannose / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism; D014312:Trisaccharides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D008024:Ligands; D008358:Mannose; D011956:Receptors, Cell Surface; D014312:Trisaccharides; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin