Achieving High Affinity towards a Bacterial Lectin through Multivalent Topological Isomers of Calix[4]arene Glycoconjugates
Achieving High Affinity towards a Bacterial Lectin through Multivalent Topological Isomers of Calix[4]arene Glycoconjugates
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DOI：
10.1002/chem.200901799
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发表时间：
2009-01-01
影响因子：
4.3
通讯作者：
Vidal, Sebastien
中科院分区：
文献类型：
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作者：
Cecioni, Samy;Lalor, Ruth;Vidal, Sebastien
通过微波辅助铜（I）催化叠氮-炔环加成（CuAAC）合成了一系列适合于糖基连接的炔衍生化杯[4]芳烃前体，制备了一类7种拓扑异构杯[4]芳烃糖缀合物.由此合成的糖缀合物包括一个单官能化衍生物，两个1，2-或1，3-二价区域异构体，一个三价和三个四价拓扑异构体的锥，部分锥或1，3-交替构象。所设计的糖缀合物被评估为来自机会性细菌铜绿假单胞菌的半乳糖结合凝集素PA-IL的配体，铜绿假单胞菌是囊性纤维化患者肺部感染的主要病原体。等温滴定量热法（ITC）确定的结合亲和力，并与凝集素的相互作用被证明是强烈依赖于价和拓扑结构。而三价缀合物显示出增强的亲和力时，与单糖模型相比，四价缀合物是迄今为止最高的亲和力的配体通过ITC测量。在杯芳烃的两面上呈现碳水化合物的拓扑结构是最有效的拓扑结构，其解离常数约为200 nm。分子模拟表明，这样的多价分子可以有效地螯合四聚体凝集素的两个结合位点;这解释了四价分子实现的亲和力增加800倍。表面等离子体共振（SPR）实验证实，这种糖缀合物是PA-IL与半乳糖基化表面结合的最强抑制剂，可用作抗粘附剂。
A family of seven topologically isomeric calix[4]arene glycoconjugates was prepared through the synthesis of a series of alkyne-derivatised calix[4]arene precursors that are suitable for the attachment of sugar moieties by microwave-assisted copper(I)-catalysed azide-alkyne cycloaddition (CuAAC). The glycoconjugates thus synthesised comprised one mono-functionalised derivative, two 1,2- or 1,3-divalent regioisomers, one trivalent and three tetravalent topoisomers in the cone, partial cone or 1,3-alternate conformations. The designed glycoconjugates were evaluated as ligands for the galactose-binding lectin PA-IL from the opportunistic bacterium Pseudomonas aeruginosa, a major causative agent of lung infections in cystic fibrosis patients. Binding affinities were determined by isothermal titration calorimetry (ITC), and the interaction with the lectin was shown to be strongly dependant on both the valence and the topology. Whereas the trivalent conjugate displayed enhanced affinity when compared to a monosaccharide model, the tetravalent conjugates are to-date the highest-affinity ligands measured by ITC. The topologies presenting carbohydrates on both faces of calixarene are the most potent ones with dissociation constants of approximately 200 nm. Molecular modelling suggests that such a multivalent molecule can efficiently chelate two of the binding sites of the tetrameric lectin; this explains the 800-fold increase of affinity achieved by the tetravalent molecule. Surface plasmon resonance (SPR) experiments confirmed that this glycoconjugate is the strongest inhibitor for binding of PA-IL to galactosylated surfaces for potential applications as an anti-adhesive agent.