Laboratoire de Synthèse Organique et Molécules Bioactives (SYBIO), Université de Strasbourg/CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux, 25 rue Becquerel, 67087 Strasbourg (France).
Chembiochem. 2013 Oct 11;14(15):2038-49. doi: 10.1002/cbic.201300283. Epub 2013 Sep 6.
In view of recent reports of a strong multivalent effect in glycosidase inhibition, a library of β-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 α-mannosidase. Generally, the evaluated multivalent iminosugars displayed comparable thermodynamic signatures of binding towards α-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.
鉴于最近有报道称糖苷酶抑制作用具有很强的多价效应，我们通过铜 (I) 催化的叠氮-炔环加成 (CuAAC) 高效合成了基于β-CD 的多价亚氨基糖库。结合等温滴定量热法 (ITC) 实验在多价亚氨基糖-酶相互作用研究中的首次应用，我们评估了这些点击簇对一系列糖苷酶的抑制特性。所改变的结构参数包括价态、外围配体结构和拓扑结构。所获得的亚氨基糖簇的抑制结果进一步强调了多价性在α-甘露糖苷酶抑制中的重要性。通常，评价的多价亚氨基糖对（菜豆）α-甘露糖苷酶显示出类似的结合热力学特征：即，大的结合焓伴随着小的正或负熵。此外，在所有测试的情况下观察到的焓熵补偿可能归因于酶-多价亚氨基糖相互作用的共同解离机制。所测量的结合化学计量表明，每个亚氨基糖簇与不超过一个蛋白质分子相互作用。
