Recently, the activity of heparan sulfate (HS) has led to the discovery of many drug candidates that have the potential to impact both medical science and human health. However, structural diversity and synthetic challenges impede the progress of HS research. Here, we report a library of novel l-iduronic acid (IdoA)-based HS mimics that are highly tunable in conformation plasticity and sulfation patterns to produce many of the functions of native HS oligosaccharides. The NMR analysis of HS mimics confirmed that 4-O-sulfation enhances the population of the ¹C₄ geometry. Interestingly, the ¹C₄ conformer becomes exclusive upon additional 2-O-sulfation. HS mimic microarray binding studies with different growth factors showed that selectivity and avidity are greatly modulated by the oligosaccharide length, sulfation code, and IdoA conformation. Particularly, we have identified 4-O-sulfated IdoA disaccharide (I-21) as a potential ligand for vascular endothelial growth factor (VEGF₁₆₅), which in a multivalent display modulated endothelial cell proliferation, migration, and angiogenesis. Overall, these results encourage the consideration of HS mimics for therapeutic applications.

中文翻译：

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l-艾杜糖醛酸低聚糖的硫酸化密码和构象可塑性模拟硫酸乙酰肝素的生物学功能

最近，硫酸乙酰肝素 (HS) 的活性导致发现了许多可能影响医学科学和人类健康的候选药物。然而，结构多样性和合成挑战阻碍了 HS 研究的进展。在这里，我们报告了一个基于l-艾杜糖醛酸 (IdoA) 的新型 HS 模拟物库，这些模拟物在构象可塑性和硫酸化模式方面高度可调，可产生天然 HS 寡糖的许多功能。HS 模拟物的NMR 分析证实4 - O-硫酸化增强了¹ C ₄几何结构的群体。有趣的是，¹ C ₄构象异构体在额外的 2- O-硫酸化。HS 模拟微阵列与不同生长因子的结合研究表明，寡糖长度、硫酸化代码和 IdoA 构象极大地调节了选择性和亲和力。特别是，我们已经确定 4 - O-硫酸化 IdoA 二糖 ( I-21 ) 作为血管内皮生长因子 (VEGF ₁₆₅ ) 的潜在配体，其在多价展示中调节内皮细胞增殖、迁移和血管生成。总体而言，这些结果鼓励考虑将 HS 模拟物用于治疗应用。