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Issue 3, 2012
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Quinoxalinoneinhibitors of the lectin DC-SIGN

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Abstract

The C-type lectin dendritic cell-specific intercellular adhesion molecule 3–grabbing nonintegrin (DC-SIGN) can serve as a docking site for pathogens on the surface of dendritic cells. Pathogen binding to DC-SIGN can have diverse consequences for the host. DC-SIGN can facilitate HIV-1 dissemination, but the interaction of Mycobacterium tuberculosis with DC-SIGN is important for host immunity. The ability of pathogens to target DC-SIGN provides impetus to identify ligands that can perturb these interactions. Here, we describe the first stable small molecule inhibitors of DC-SIGN. These inhibitors were derived from a collection of quinoxalinones, which were assembled using a tandem cross metathesis-hydrogenation sequence. To assess the ability of these small molecules to block DC-SIGN-mediated glycan adhesion and internalization, we developed a sensitive flow cytometry assay. Our results reveal that the quinoxalinones are effective inhibitors of DC-SIGN–glycan interactions. These compounds block both glycan binding to cells and glycan internalization. We anticipate that these non-carbohydrate inhibitors can be used to elucidate the role of DC-SIGN in pathogenesis and immune function.

Graphical abstract: Quinoxalinone inhibitors of the lectin DC-SIGN

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Supplementary files

Article information


Submitted
07 Oct 2011
Accepted
23 Nov 2011
First published
24 Nov 2011

Chem. Sci., 2012,3, 772-777
Article type
Edge Article

Quinoxalinone inhibitors of the lectin DC-SIGN

S. L. Mangold, L. R. Prost and L. L. Kiessling, Chem. Sci., 2012, 3, 772 DOI: 10.1039/C2SC00767C

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