Glycosaminoglycans (GAGs) play critical roles in diverse processes ranging from viral infection to neuroregeneration. Their regiospecific sulfation patterns, which are generated by sulfotransferases, are key structural determinants that underlie their biological activity. Small-molecule modulators of these sulfotransferases could serve as powerful tools for understanding the physiological functions of GAGs, as well as potential therapeutic leads for human diseases. Here, we report the development of the first cell-permeable, small-molecule inhibitor selective for GAG sulfotransferases, which was obtained using a high-throughput screen targeted against Chst15, the sulfotransferase responsible for biosynthesis of chondroitin sulfate-E (CS-E). We demonstrate that the molecule specifically inhibits GAG sulfotransferases in vitro, decreases CS-E and overall sulfation levels on cell-surface and secreted chondroitin sulfate proteoglycans (CSPGs), and reverses CSPG-mediated inhibition of axonal growth. These studies pave the way toward a new set of pharmacological tools for interrogating GAG sulfation-dependent processes and may represent a novel therapeutic approach for neuroregeneration.

中文翻译：

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糖胺聚糖硫酸化的小分子调节剂的发现。

糖胺聚糖（GAG）在从病毒感染到神经再生的各种过程中发挥关键作用。由磺基转移酶产生的它们的区域特异性硫酸化模式是构成其生物学活性的关键结构决定因素。这些磺基转移酶的小分子调节剂可作为了解GAG生理功能以及人类疾病潜在治疗方法的有力工具。在这里，我们报告了第一种对GAG磺基转移酶具有选择性的细胞渗透性小分子抑制剂的开发，该抑制剂是使用针对Chst15（负责硫酸软骨素E（CS-E）生物合成的磺基转移酶）的高通量筛选获得的。我们证明该分子特异性抑制GAG磺基转移酶在体外，可降低细胞表面和分泌的软骨素硫酸盐蛋白聚糖（CSPG）的CS-E和总体硫酸盐水平，并逆转CSPG介导的轴突生长抑制作用。这些研究为探寻GAG硫酸盐依赖过程的新药理学方法铺平了道路，并且可能代表了一种神经再生的新型治疗方法。