Issue 10, 2015

Small molecule antagonists of cell-surface heparan sulfate and heparin–protein interactions

Abstract

Surfen, bis-2-methyl-4-amino-quinolyl-6-carbamide, was previously reported as a small molecule antagonist of heparan sulfate (HS), a key cell-surface glycosaminoglycan found on all mammalian cells. To generate structure–activity relationships, a series of rationally designed surfen analogs was synthesized, where its dimeric structure, exocyclic amines, and urea linker region were modified to probe the role of each moiety in recognizing HS. An in vitro assay monitoring inhibition of fibroblast growth factor 2 binding to wild-type CHO cells was utilized to quantify interactions with cell surface HS. The dimeric molecular structure of surfen and its aminoquinoline ring systems was essential for its interaction with HS, and certain dimeric analogs displayed higher inhibitory potency than surfen and were also shown to block downstream FGF signaling in mouse embryonic fibroblast cells. These molecules were also able to antagonize other HS–protein interactions including the binding of soluble RAGE to HS. Importantly, selected molecules were shown to neutralize heparin and other heparinoids, including the synthetic pentasaccharide fondaparinux, in a factor Xa chromogenic assay and in vivo in mice. These results suggest that small molecule antagonists of heparan sulfate and heparin can be of therapeutic potential for the treatment of disorders involving glycosaminoglycan–protein interactions.

Graphical abstract: Small molecule antagonists of cell-surface heparan sulfate and heparin–protein interactions

Supplementary files

Article information

Article type
Edge Article
Submitted
04 Apr 2015
Accepted
21 Jul 2015
First published
29 Jul 2015
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2015,6, 5984-5993

Small molecule antagonists of cell-surface heparan sulfate and heparin–protein interactions

R. J. Weiss, P. L. S. M. Gordts, D. Le, D. Xu, J. D. Esko and Y. Tor, Chem. Sci., 2015, 6, 5984 DOI: 10.1039/C5SC01208B

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