Selective targeting of dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) with mannose-based glycomimetics:synthesis and interaction studies of bis(benzylamide) derivatives of a pseudomannobioside

Varga, Norbert, Sutkeviciute, Ieva, Guzzi, Cinzia, McGeagh, John, Petit-Haertlein, Isabelle, Gugliotta, Serena, Weiser, Jörg, Angulo, Jesús ORCID: https://orcid.org/0000-0001-7250-5639, Fieschi, Franck and Bernardi, Anna (2013) Selective targeting of dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) with mannose-based glycomimetics:synthesis and interaction studies of bis(benzylamide) derivatives of a pseudomannobioside. Chemistry - A European Journal, 19 (15). pp. 4786-4797. ISSN 0947-6539

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Abstract

Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and Langerin are C-type lectins of dendritic cells (DCs) that share a specificity for mannose and are involved in pathogen recognition. HIV is known to use DC-SIGN on DCs to facilitate transinfection of T-cells. Langerin, on the contrary, contributes to virus elimination; therefore, the inhibition of this latter receptor is undesired. Glycomimetic molecules targeting DC-SIGN have been reported as promising agents for the inhibition of viral infections and for the modulation of immune responses mediated by DC-SIGN. We show here for the first time that glycomimetics based on a mannose anchor can be tuned to selectively inhibit DC-SIGN over Langerin. Based on structural and binding studies of a mannobioside mimic previously described by us (2), a focused library of derivatives was designed. The optimized synthesis gave fast and efficient access to a group of bis(amides), decorated with an azide-terminated tether allowing further conjugation. SPR inhibition tests showed improvements over the parent pseudomannobioside by a factor of 3-4. A dimeric, macrocyclic structure (11) was also serendipitously obtained, which afforded a 30-fold gain over the starting compound (2). The same ligands were tested against Langerin and found to exhibit high selectivity towards DC-SIGN. Structural studies using saturation transfer difference NMR spectroscopy (STD-NMR) were performed to analyze the binding mode of one representative library member with DC-SIGN. Despite the overlap of some signals, it was established that the new ligand interacts with the protein in the same fashion as the parent pseudodisaccharide. The two aromatic amide moieties showed relatively high saturation in the STD spectrum, which suggests that the improved potency of the bis(amides) over the parent dimethyl ester can be attributed to lipophilic interactions between the aromatic groups of the ligand and the binding site of DC-SIGN.

Item Type:	Article
Additional Information:	Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Uncontrolled Keywords:	dc-sign,glycomimetics,hiv,nmr spectroscopy,proteins,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School:	Faculty of Science > School of Pharmacy
UEA Research Groups:	Faculty of Science > Research Groups > Drug Delivery and Pharmaceutical Materials (former - to 2017) Faculty of Science > Research Groups > Pharmaceutical Materials and Soft Matter
Depositing User:	Pure Connector
Date Deposited:	21 Oct 2013 15:38
Last Modified:	24 Oct 2022 04:50
URI:	https://ueaeprints.uea.ac.uk/id/eprint/43777
DOI:	10.1002/chem.201202764

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