Human immunodeficiency virus (HIV) is still a huge health problem, causing the death of over 1 million people per year. The search for HIV-entry inhibitors represents a promising challenge to prevent HIV infection. In this field, DC-SIGN, a carbohydrate-recognizing receptor expressed at the surface of the mucosal dendritic cells and involved in the early stages of HIV infection, is an important cellular target. The use of artificial molecules presenting multivalent carbohydrate moieties, able to interact with DC-SIGN with good affinity, should represent a therapeutic strategy in order to prevent HIV attachment to dendritic cells. Here we present a library of multivalent pseudo-glycodendrimers characterized by rigid molecular rods that rationally space active ligands, with the aim to exploit both the statistical rebinding and the chelating binding modes. Compounds were synthesised by varying the length of the rigid rod, the nature as well as the valency of the sugar moieties and the linkers flexibility. The optimal combination of active monovalent ligand, scaffold and valency led to a nanomolar inhibitor of DC-SIGN-mediated adhesion of HIV on cells. Compounds' biological performances were evaluated through Surface Plasmon Resonance Inhibition assays and trans-infection inhibition assays; the interaction between artificial compounds and DC-SIGN expressing cells was evaluated through confocal micoscopy, given the intrinsic fluorescence of the rods. Morphological behaviour of glycodendrimers was investigated using several analytical techniques, demonstrating that they are mainly monomers in solution, despite their amphiphilic structure. Finally, modifications of monovalent ligands were performed in order to improve compounds selectivity vs Langerin.
PSEUDO-GLYCODENDRIMERS CONTAINING A MOLECULAR ROD CORE: SYNTHESIS, CHARACTERIZATION AND DC-SIGN ANTAGONISM / S. Ordanini ; tutor: A. Bernardi ; coordinator: E. Licandro. - Milano : Università degli studi di Milano. DIPARTIMENTO DI CHIMICA, 2015 Mar 30. ((27. ciclo, Anno Accademico 2014.
|Titolo:||PSEUDO-GLYCODENDRIMERS CONTAINING A MOLECULAR ROD CORE: SYNTHESIS, CHARACTERIZATION AND DC-SIGN ANTAGONISM|
|Supervisori e coordinatori interni:||LICANDRO, EMANUELA|
|Data di pubblicazione:||30-mar-2015|
|Parole Chiave:||HIV; DC-SIGN; multivalency; glycomimetic|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
|Citazione:||PSEUDO-GLYCODENDRIMERS CONTAINING A MOLECULAR ROD CORE: SYNTHESIS, CHARACTERIZATION AND DC-SIGN ANTAGONISM / S. Ordanini ; tutor: A. Bernardi ; coordinator: E. Licandro. - Milano : Università degli studi di Milano. DIPARTIMENTO DI CHIMICA, 2015 Mar 30. ((27. ciclo, Anno Accademico 2014.|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.13130/ordanini-stefania_phd2015-03-30|
|Appare nelle tipologie:||Tesi di dottorato|