Surfen, a small molecule antagonist of heparan sulfate

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-09, Vol.105 (35), p.13075-13080
• Main Authors: Schuksz, Manuela, Fuster, Mark M, Brown, Jillian R, Crawford, Brett E, Ditto, David P, Lawrence, Roger, Glass, Charles A, Wang, Lianchun, Tor, Yitzhak, Esko, Jeffrey D
• Format: Article
• Language: English
• Subjects: Animals; Binding sites; Biological Sciences; Carbohydrates; Cell Adhesion - drug effects; Cell culture; CHO Cells; Cricetinae; Cricetulus; Endothelial cells; Factor Xa - metabolism; Fibroblast Growth Factor 2 - metabolism; Glycosaminoglycans - metabolism; Heparin; Heparin Lyase - metabolism; Heparin, Low-Molecular-Weight - metabolism; Heparitin Sulfate - antagonists & inhibitors; Herpesvirus 1, Human - metabolism; Human herpesvirus 1; Humans; Infections; Low molecular weights; Mice; Molecular weight; Molecules; Neovascularization, Physiologic - drug effects; Neutralization Tests; Protamines; Proteins; Receptors; Signal Transduction - drug effects; Solutions; Sulfates; Sulfotransferases - metabolism; Sulfur - metabolism; Swine; Urea - analogs & derivatives; Urea - chemistry; Urea - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0805862105

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 VEGF₁₆₅-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.