Small molecule antagonists of cell-surface heparan sulfate and heparin-protein interactions.
Small molecule antagonists of cell-surface heparan sulfate and heparin-protein interactions.
复制标题
细胞表面硫酸盐和肝素 - 蛋白质相互作用的小分子拮抗剂。
DOI：
10.1039/c5sc01208b
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发表时间：
2015-10-01
期刊：
影响因子：
8.4
通讯作者：
Tor Y
中科院分区：
文献类型：
--
作者：
Weiss RJ;Gordts PL;Le D;Xu D;Esko JD;Tor Y
合成了一系列设计合理的SURFEN类似物，并将其用于糖胺聚糖-蛋白质相互作用的拮抗剂，包括中和肝素的合成五糖类似物磺达肝素的抗凝血活性。苏尔芬，双-2-甲基-4-氨基-喹啉-6-尿素，是硫酸肝素(HS)的小分子拮抗剂，是一种存在于所有哺乳动物细胞表面的关键糖胺聚糖。为了建立构效关系，合成了一系列设计合理的Surfen类似物，对其二聚体结构、外环胺和尿素连接区进行了修饰，以探讨每个部分在识别HS中的作用。利用一种监测成纤维细胞生长因子2与野生型CHO细胞结合抑制的体外实验来量化与细胞表面HS的相互作用。SURFEN及其氨基喹啉环系的二聚体分子结构是其与HS相互作用所必需的，某些二聚体类似物显示出比SURFEN更强的抑制效力，并被证明能阻断小鼠胚胎成纤维细胞的下游成纤维细胞生长因子信号转导。这些分子还能拮抗其他HS-蛋白质相互作用，包括可溶性RAGE与HS的结合。重要的是，在因子Xa显色试验和小鼠体内实验中，选定的分子被证明能够中和肝素和其他肝素，包括合成的五糖磺达肝素。这些结果表明，硫酸乙酰肝素和肝素的小分子拮抗剂可用于治疗涉及糖胺聚糖-蛋白质相互作用的疾病。
A series of rationally designed surfen analogs were synthesized and utilized as antagonists of glycosaminoglycan–protein interactions, including the neutralization of the anticoagulant activity of fondaparinux, a synthetic pentasaccharide analog of heparin. 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.