Department of Chemistry, University of Hamburg, Organic Chemistry, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.
Chembiochem. 2012 Feb 13;13(3):443-50. doi: 10.1002/cbic.201100642. Epub 2012 Jan 5.
Glycosyltransferases play an important role in the formation of oligosaccharides and glycoconjugates. To find suitable and selective inhibitors for this class of enzymes is still challenging. Here, we describe a novel concept that allows the design of inhibitors based on the structure of the donor substrate binding pocket. As a first step we describe the design, synthesis and analysis of inhibitors of the human blood group B galactosyltransferase (GTB). This enzyme served as a model system to study the concept, which can be used for easy access of glycosyltransferase inhibitors in general. In silico docking of bicyclic heteroaromatic ligands to GTB and experimental verification of binding affinities by saturation transfer difference NMR (STD NMR) spectroscopy gave 9-N-pentityl uric acid derivatives as non-ionic mimics of UDP. Two derivatives were synthesized and showed inhibitory activity for GTB as determined by competitive STD NMR experiments and by a radiolabeled enzyme assay.
糖基转移酶在寡糖和糖缀合物的形成中发挥着重要作用。寻找此类酶的合适和选择性抑制剂仍然具有挑战性。在这里，我们描述了一种新的概念，允许根据供体底物结合口袋的结构设计抑制剂。作为第一步，我们描述了人血型 B 半乳糖基转移酶 (GTB) 的抑制剂的设计、合成和分析。该酶作为模型系统用于研究该概念，该概念可用于一般糖基转移酶抑制剂的便捷获取。通过饱和转移差异 NMR（STD NMR）光谱对双环杂芳烃配体与 GTB 的计算机对接以及结合亲和力的实验验证，得到了 9-N-戊基尿酸衍生物作为 UDP 的非离子模拟物。合成了两种衍生物，并通过竞争性 STD NMR 实验和放射性标记酶测定确定了它们对 GTB 的抑制活性。
