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The main aim of this WP will be the preparation of monovalent ligands to be attached to the corresponding multivalent scaffolds supplied by groups in WP3. These ligands will be selected starting from available structural knowledge of the DC-SIGN target and optimized with the help of computational studies performed by Anterio consult&research GmbH. This partner will screen libraries of compounds with powerful computational tools based on docking studies to allow the selection of promising candidates as ligands for DC-SIGN receptor. Selectivity versus Langherin will also be tested in silico. The synthetic groups in this WP will provide the following approaches:

a. The Berlin partner will prepare complex oligosaccharides (fuco- and manno-) by automated solid phase methodology. The products of these syntheses are released presenting an n-pentenyl group on the reducing end of the oligosaccharide that can be used to install reactive groups for anchoring oligosaccharides to a surface, or to dendrimers.

b. This powerful solid-phase methodology will be complemented by solution-phase and chemoenzymatic syntheses by the Oxford Group. Glycosylation-cascade and enzymatic methodologies will be used by this partner to create DC-SIGN type ligands using mannosylation and glucosylation technology coupled with new highly selective phosphorylation protocols. These methods will allow access to oligosaccharides containing non-natural alterations (deoxygenation, fluorination, phosphonate).

c. Partners in Prague and Milan will be in charge of the preparation of oligosaccharide mimics that will be used to address the issue of in vivo degradation of drug candidates by glycosylhydrolases. The first approach will be developed by the Czech group and it will be based on the preparation of C-glycosides. The Italian team’s strategy will be based on the preparation of pseudo-oligosaccharides and unnatural neo-glycoconjugates containing mannose or fucose anchors.