The Multivalent Effect in Glycosidase Inhibition: Probing the Influence of Valency, Peripheral Ligand Structure, and Topology with Cyclodextrin-Based Iminosugar Click Clusters
The Multivalent Effect in Glycosidase Inhibition: Probing the Influence of Valency, Peripheral Ligand Structure, and Topology with Cyclodextrin-Based Iminosugar Click Clusters
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DOI：
10.1002/cbic.201300283
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发表时间：
2013-10-11
期刊：
影响因子：
3.2
通讯作者：
Compain, Philippe
中科院分区：
文献类型：
--
作者：
Decroocq, Camille;Joosten, Antoine;Compain, Philippe
鉴于最近报道的一个强大的多价作用，在糖苷酶抑制，库-CD为基础的多价亚氨基糖已被有效地合成的方式Cu-I-催化的叠氮化物-炔环加成（CuAAC）。结合等温滴定量热法（ITC）实验的多价亚氨基糖-酶相互作用的研究的第一个应用程序，这些点击集群的抑制特性进行了评估的一个面板上的glycoproteinases。变化的结构参数包括化合价、外周配体结构和拓扑结构。用亚氨基糖簇获得的抑制结果进一步突出了多价性在抑制β-甘露糖苷酶中的重要性。一般来说，评估的多价亚氨基糖显示出相当的热力学特征的结合朝向-甘露糖苷酶（刀豆）：也就是说，大的负熵的络合耦合小熵的任何一个符号。此外，在所有测试的情况下观察到的熵-熵补偿可以归因于酶-多价亚氨基糖相互作用的共同解离机制。测得的结合化学计量表明，每个亚胺糖簇相互作用不超过一个蛋白质分子。
In view of recent reports of a strong multivalent effect in glycosidase inhibition, a library of -CD-based multivalent iminosugars has been efficiently synthesized by way of Cu-I-catalyzed azide-alkyne cycloaddition (CuAAC). In combination with the first application of isothermal titration calorimetry (ITC) experiments to the study of multivalent iminosugar-enzyme interactions, the inhibition properties of these click clusters were evaluated on a panel of glycosidases. The structural parameters that were varied include valency, peripheral ligand structure, and topology. The inhibition results obtained with the iminosugar clusters further highlight the importance of multivalency in the inhibition of -mannosidase. Generally, the evaluated multivalent iminosugars displayed comparable thermodynamic signatures of binding towards -mannosidase (Jack bean): that is, large negative enthalpies of complexation coupled with small entropies of either sign. In addition, the enthalpy-entropy compensation observed in all tested cases may be attributed to a common mechanism of dissociation for the enzyme-multivalent iminosugar interactions. The measured binding stoichiometries indicated that each iminosugar cluster interacts with no more than one protein molecule.