Heparan sulfate mimicry: a synthetic glycoconjugate that recognizes the heparin binding domain of interferon-gamma inhibits the cytokine activity.
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 (IFNgamma), 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 IFNgamma monomer. Based on this template, we have synthesized a set of glycoconjugate mimetics and evaluated their ability to interact with IFNgamma. One of these molecules, composed of two authentic N-sulfated octasaccharides linked to each other through a 50-Angstroms-long spacer termed 2O(10), displays high affinity for the cytokine and inhibits IFNgamma-HS binding with an IC(50) of 35-40 nm. Interestingly, this molecule also inhibits the binding of IFNgamma to its cellular receptor. Thus, in addition to its ability to delocalize the cytokine from cell surface-associated HS, this compound has direct anti-IFNgamma activity. Altogether, our results represent the first synthetic HS-like molecule that targets a cytokine, strongly validating the HS structural determinants for IFNgamma recognition, providing a new strategy to inhibit IFNgamma 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.
Sarrazin
Stéphane
S
Institut de Biologie Structurale, Commissariat à l'Energie Atomique-CNRS, Université Joseph Fourier, Unité Mixte de Recherche 5075, Grenoble, France.
Bonnaffé
David
D
Lubineau
André
A
Lortat-Jacob
Hugues
H
D000595:Amino Acid Sequence; D000818:Animals; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002460:Cell Line; D006001:Glycoconjugates / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006493:Heparin / Q000378:metabolism*; D006497:Heparan Sulfate / Q000737:chemistry*; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D018716:Molecular Mimicry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014721:Vesicular stomatitis Indiana virus
D006001:Glycoconjugates; D006493:Heparin; D006497:Heparan Sulfate; D007371:Interferon-gamma