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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Surfen, a small molecule antagonist of heparan sulfate
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Surfen, a small molecule antagonist of heparan sulfate

机译：Surfen，硫酸乙酰肝素的小分子拮抗剂

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摘要

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-ll 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.
机译：在寻找硫酸乙酰肝素的小分子拮抗剂时，我们检查了bis-2-methyl-4-amino-quinolyl-6-carbamide（也称为surfen）的活性。基于荧光的滴定表明，surfen与糖胺聚糖结合，结合程度根据电荷密度的增加而依次为肝素>硫酸皮肤素>硫酸乙酰肝素>硫酸软骨素。肝素中的所有带电基团（N-硫酸盐，O-硫酸盐和羧基）都有助于结合，这与Surfen静电相互作用的想法一致。 Surfen中和了普通肝素和低分子量肝素的抗凝活性，并在体外抑制了酶促硫酸化和降解反应。在培养的细胞中添加surfen可以阻止FGF2结合和信号传导，而FGF2结合和信号传导依赖于细胞表面硫酸乙酰肝素，并阻止FGF2-和VEGF_（165）介导的基质胶中内皮细胞的萌芽。 Surfen还阻断了硫酸乙酰肝素介导的细胞与纤连蛋白Hep-II结构域的粘附，并阻止了依赖于糖蛋白D与硫酸乙酰肝素相互作用的HSV-1的感染。这些发现证明了鉴定硫酸乙酰肝素的小分子拮抗剂的可行性，并提高了开发药理剂治疗涉及糖胺聚糖-蛋白质相互作用的疾病的可能性。

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