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Issue 1, 2016
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Detection and quantitative analysis of two independent binding modes of a small ligand responsible for DC-SIGN clustering

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Abstract

DC-SIGN (dendritic cell-specific ICAM-3 grabbing non-integrin) is a C-type lectin receptor (CLR) present, mainly in dendritic cells (DCs), as one of the major pattern recognition receptors (PRRs). This receptor has a relevant role in viral infection processes. Recent approaches aiming to block DC-SIGN have been presented as attractive anti-HIV strategies. DC-SIGN binds mannose or fucose-containing carbohydrates from viral proteins such as the HIV envelope glycoprotein gp120. We have previously demonstrated that multivalent dendrons bearing multiple copies of glycomimetic ligands were able to inhibit DC-SIGN-dependent HIV infection in cervical explant models. Optimization of glycomimetic ligands requires detailed characterization and analysis of their binding modes because they notably influence binding affinities. In a previous study we characterized the binding mode of DC-SIGN with ligand 1, which shows a single binding mode as demonstrated by NMR and X-ray crystallography. In this work we report the binding studies of DC-SIGN with pseudotrisaccharide 2, which has a larger affinity. Their binding was analysed by TR-NOESY and STD NMR experiments, combined with the CORCEMA-ST protocol and molecular modelling. These studies demonstrate that in solution the complex cannot be explained by a single binding mode. We describe the ensemble of ligand bound modes that best fit the experimental data and explain the higher inhibition values found for ligand 2.

Graphical abstract: Detection and quantitative analysis of two independent binding modes of a small ligand responsible for DC-SIGN clustering

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Publication details

The article was received on 28 Sep 2015, accepted on 19 Nov 2015 and first published on 19 Nov 2015


Article type: Paper
DOI: 10.1039/C5OB02025E
Author version available: Download Author version (PDF)
Citation: Org. Biomol. Chem., 2016,14, 335-344
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    Detection and quantitative analysis of two independent binding modes of a small ligand responsible for DC-SIGN clustering

    C. Guzzi, P. Alfarano, I. Sutkeviciute, S. Sattin, R. Ribeiro-Viana, F. Fieschi, A. Bernardi, J. Weiser, J. Rojo, J. Angulo and P. M. Nieto, Org. Biomol. Chem., 2016, 14, 335
    DOI: 10.1039/C5OB02025E

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