期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 280, 期 45, 页码 37558-37564出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M507729200
关键词
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Cell-associated heparan sulfate (HS) is endowed with the remarkable ability to bind numerous proteins. As such, it represents a unique system that integrates signaling from circulating ligands with cellular receptors. This polysaccharide is extraordinary complex, and examples that define the structure-function relationship of HS are limited. In particular, it remains difficult to understand the structures by which HS interact with proteins. Among them, interferon-gamma(IFN gamma), a dimeric cytokine, binds to a complex oligosaccharide motif encompassing a N-acetylated glucosamine-rich domain and two highly sulfated sequences, each of which binds to one IFN gamma monomer. Based on this template, we have synthesized a set of glycoconjugate mimetics and evaluated their ability to interact with IFN gamma. One of these molecules, composed of two authentic N-sulfated octasaccharides linked to each other through a 50-angstrom-long spacer termed 2O(10), displays high affinity for the cytokine and inhibits IFN gamma-HS binding with an IC50 of 35 - 40 nM. Interestingly, this molecule also inhibits the binding of IFN gamma to its cellular receptor. Thus, in addition to its ability to delocalize the cytokine from cell surface-associated HS, this compound has direct anti-IFN gamma activity. Altogether, our results represent the first synthetic HS-like molecule that targets a cytokine, strongly validating the HS structural determinants for IFN gamma recognition, providing a new strategy to inhibit IFN gamma in a number of diseases in which the cytokine has been identified as a target, and reinforcing the view that it is possible to create tailor-made sequences based on the HS template to isolate therapeutic activities.
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