WP3 - Multivalent Systems


WP3 will create carbohydrate multivalent tools using ligands prepared by WP1 and selected by WP2 or from natural sources. DC-SIGN recognizes the highly glycosylated envelop proteins of several pathogens through a calcium-dependent, multivalent binding mode of the Carbohydrate Recognition Domain (CRD) by the protein. This statement highlights the importance and logic of the multivalent approach that is suggested in this application for the design of new tools based on carbohydrates for this receptor.

a. The Seville team will prepare a series of dendritic cores in a stepwise way based on Boltorn structures to obtain discrete materials (monodisperse) of different generations that will present different multivalency. These systems will be functionalyzed at the surface using carbohydrates and carbohydrate mimics prepared by teams in WP1 providing carbohydrate multivalent systems with high affinity for DC-SIGN.

b. The Oxford Group will prepare glycodendriproteins using the ligands provided by WP1 and the dendrimer technology developed by the Seville and Oxford groups. The protein-dendrimer-carbohydrate attachment (ligation) methods developed in Oxford will be applied making use of disulfide, cycloaddition and amide forming ligation methods.

c. DC4U will produce the natural glycoproteins that bind to DC-SIGN and mediate cellular DC-T cell and DC-neutrophil interactions. The designed carbohydrate structures will be investigated for their potency to interfere with natural interactions of DC-SIGN with ICAM-3 and CEACAM1. This will give detailed information on the potency and specificity of the carbohydrate structures to only inhibit DC-SIGN pathogen interactions.