A Hexasaccharide Containing Rare 2-O-Sulfate-Glucuronic Acid Residues Selectively Activates Heparin Cofactor II.
A Hexasaccharide Containing Rare 2-O-Sulfate-Glucuronic Acid Residues Selectively Activates Heparin Cofactor II.
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DOI：
10.1002/anie.201609541
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发表时间：
2017-02-20
期刊：
影响因子：
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通讯作者：
Desai UR
中科院分区：
文献类型：
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作者：
Sankarayanarayanan NV;Strebel TR;Boothello RS;Sheerin K;Raghuraman A;Sallas F;Mosier PD;Watermeyer ND;Oscarson S;Desai UR
选择性靶向肝素辅因子II（HCII）（人血浆中存在的关键丝氨酸蛋白酶抑制剂）的糖胺聚糖（GAG）序列仍然未知。使用46656硫酸乙酰肝素六糖库的计算策略，我们确定了一个罕见的序列组成的连续葡萄糖醛酸2-O-硫酸酯残基作为选择性靶向HCII。这种和其他四种独特的六糖是化学合成的。发现设计的序列激活HCII ca。250倍，而不考虑抗凝血酶，一种密切相关的丝氨酸蛋白酶抑制剂，基本上未活化。这组罕见的设计六糖将有助于理解HCII功能。更重要的是，我们的研究结果首次表明，严格使用计算技术可以发现可以选择性靶向GAG结合蛋白的独特GAG序列，这可能会导致化学生物学或药物发现工具。
Glycosaminoglycan (GAG) sequences that selectively target heparin cofactor II (HCII), a key serpin present in human plasma, remain unknown. Using a computational strategy on a library of 46 656 heparan sulfate hexasaccharides we identified a rare sequence consisting of consecutive glucuronic acid 2‐O‐sulfate residues as selectively targeting HCII. This and four other unique hexasaccharides were chemically synthesized. The designed sequence was found to activate HCII ca. 250‐fold, while leaving aside antithrombin, a closely related serpin, essentially unactivated. This group of rare designed hexasaccharides will help understand HCII function. More importantly, our results show for the first time that rigorous use of computational techniques can lead to discovery of unique GAG sequences that can selectively target GAG‐binding protein(s), which may lead to chemical biology or drug discovery tools.