title: 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. Anin vitroassay 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 andin vivoin 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, 92093-0358, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Weiss
authors.affiliation: Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, 92093-0687, USA.
authors.forename: Philip L S M
authors.initials: PL
authors.lastname: Gordts
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, 92093-0612, USA; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, 92093-0687, USA.
authors.forename: Dzung
authors.initials: D
authors.lastname: Le
authors.affiliation: Department of Oral Biology, University at Buffalo, Buffalo, NY, 14260-1660, USA.
authors.forename: Ding
authors.initials: D
authors.lastname: Xu
authors.affiliation: Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, 92093-0687, USA; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, 92093-0687, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, 92093-0358, USA; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, 92093-0687, USA.
authors.forename: Yitzhak
authors.initials: Y
authors.lastname: Tor