Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense de Madrid, Plz. Ramón y Cajal s/n, Madrid C.P. 28040, Spain.
Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense de Madrid, Plz. Ramón y Cajal s/n, Madrid C.P. 28040, Spain.
Bioorg Chem. 2023 Dec;141:106913. doi: 10.1016/j.bioorg.2023.106913. Epub 2023 Oct 10.
Multivalent glycodendrons are valuable tools to mimic many structural and functional features of cell-surface glycoconjugates and its focal position scaffolds represent important components to increase specificity and affinity. Previous work in our group described the preparation of a tetravalent glucuronic acid dendron that binds with good affinity to Dengue virus envelope protein (K = 22 μM). Herein, the chemical synthesis and binding analysis of a new library of potent glucuronic acid dendrons bearing different functional group at the focal position and different level of multivalency are described. Their chemical synthesis was performed sequentially in three stages and with good yields. Namely a) the chemical synthesis of the oligo and polyalkynyl scaffolds, b) assembling with fully protected glucuronic acid-based azide units by using a microwave assisted copper-catalysed azide-alkyne cycloaddition reaction and c) sequential deprotection of hydroxyl and carboxylic acid groups. Surface Plasmon Resonance studies have demonstrated that the valency and the focal position functional group exert influence on the interaction with Dengue virus envelope protein. Molecular modelling studies were carried out in order to understand the binding observed. This work reports an efficient glycodendrons chemical synthesis that provides appropriate focal position functional group and multivalence, that offer an easy and versatile strategy to find new active compounds against Dengue virus.
多价糖树状大分子是模拟细胞表面糖缀合物的许多结构和功能特征的有价值工具，其焦点位置支架代表了增加特异性和亲和力的重要组成部分。我们小组之前的工作描述了四价葡萄糖醛酸树状大分子的制备，该分子与登革热病毒包膜蛋白具有良好的亲和力（K=22μM）。本文描述了一系列新的具有不同焦点位置官能团和不同多价程度的有效葡萄糖醛酸树状大分子的化学合成和结合分析。它们的化学合成分三个阶段进行，收率良好。即 a) 寡聚和多炔基支架的化学合成，b) 通过微波辅助铜催化叠氮-炔环加成反应将全保护的基于葡萄糖醛酸的叠氮单元组装在一起，c) 羟基和羧酸基团的顺序脱保护。表面等离子体共振研究表明，价数和焦点位置官能团对与登革热病毒包膜蛋白的相互作用有影响。进行了分子建模研究以了解观察到的结合。这项工作报道了一种有效的糖树状大分子化学合成方法，该方法提供了适当的焦点位置官能团和多价性，为寻找针对登革热病毒的新型有效化合物提供了一种简单而通用的策略。
