title: Surfen, a small molecule antagonist of heparan sulfate.
abstract: In a search for small molecule antagonists of heparan sulfate, we examined the activity of bis-2-methyl-4-amino-quinolyl-6-carbamide, also known as surfen. Fluorescence-based titrations indicated that surfen bound to glycosaminoglycans, and the extent of binding increased according to charge density in the order heparin > dermatan sulfate > heparan sulfate > chondroitin sulfate. All charged groups in heparin (N-sulfates, O-sulfates, and carboxyl groups) contributed to binding, consistent with the idea that surfen interacted electrostatically. Surfen neutralized the anticoagulant activity of both unfractionated and low molecular weight heparins and inhibited enzymatic sulfation and degradation reactions in vitro. Addition of surfen to cultured cells blocked FGF2-binding and signaling that depended on cell surface heparan sulfate and prevented both FGF2- and VEGF(165)-mediated sprouting of endothelial cells in Matrigel. Surfen also blocked heparan sulfate-mediated cell adhesion to the Hep-II domain of fibronectin and prevented infection by HSV-1 that depended on glycoprotein D interaction with heparan sulfate. These findings demonstrate the feasibility of identifying small molecule antagonists of heparan sulfate and raise the possibility of developing pharmacological agents to treat disorders that involve glycosaminoglycan-protein interactions.
authors: Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California at San Diego, La Jolla, CA 92093-0687, USA.
authors: Manuela
authors: M
authors: Schuksz
authors: Mark M
authors: MM
authors: Fuster
authors: Jillian R
authors: JR
authors: Brown
authors: Brett E
authors: BE
authors: Crawford
authors: David P
authors: DP
authors: Ditto
authors: Roger
authors: R
authors: Lawrence
authors: Charles A
authors: CA
authors: Glass
authors: Lianchun
authors: L
authors: Wang
authors: Yitzhak
authors: Y
authors: Tor
authors: Jeffrey D
authors: JD
authors: Esko
mesh_terms: D000818:Animals; D016466:CHO Cells; D002448:Cell Adhesion / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D015951:Factor Xa / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D019763:Heparin Lyase / Q000378:metabolism; D006495:Heparin, Low-Molecular-Weight / Q000378:metabolism; D006497:Heparan Sulfate / Q000037:antagonists & inhibitors*; D018259:Herpesvirus 1, Human / Q000378:metabolism; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009500:Neutralization Tests; D015398:Signal Transduction / Q000187:drug effects; D012996:Solutions; D015238:Sulfotransferases / Q000378:metabolism; D013455:Sulfur / Q000378:metabolism; D013552:Swine; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D015951:Factor Xa; D016222:Fibroblast Growth Factor 2; D006025:Glycosaminoglycans; D019763:Heparin Lyase; D006495:Heparin, Low-Molecular-Weight; D006497:Heparan Sulfate; D012996:Solutions; D015238:Sulfotransferases; D013455:Sulfur; D014508:Urea; C010850:aminoquinuride