Martin Harlei, Masterson Hannah, Kavanagh Kevin, Velasco-Torrijos Trinidad
Department of Chemistry, Maynooth University, Maynooth, W23VP22 Co. Kildare, Ireland.
Department of Biology, Maynooth University, Maynooth, W23VP22 Co. Kildare, Ireland.
Pathogens. 2021 May 8;10(5):572. doi: 10.3390/pathogens10050572.
Multivalency is a strategy commonly used by medicinal carbohydrate chemists to increase the affinity of carbohydrate-based small molecules for their protein targets. Although this approach has been very successful in enhancing binding to isolated carbohydrate-binding proteins, anticipating the multivalent presentations that will improve biological activity in cellular assays remains challenging. In this work we investigate linear molecular scaffolds for the synthesis of a low valency presentation of a divalent galactoside , previously identified by us as an inhibitor of the adhesion of opportunistic fungal pathogen to buccal epithelial cells (BECs). Adhesion inhibition assays revealed that multivalent glycoconjugate is more effective at blocking adherence to BECs upon initial exposure to epithelial cells. Interestingly, did not seem to have any effect when it was pre-incubated with yeast cells, in contrast to the original lead compound , which caused a 25% reduction of adhesion. In competition assays, where yeast cells and BECs were co-incubated, multivalent glycoconjugate inhibited up to 49% adherence in a dose-dependent manner. The combined effect of compound towards both yeast cells and BECs allowed it to achieve over 60% inhibition of the adhesion of to BECs in competition assays.
多价性是药用碳水化合物化学家常用的一种策略，用于提高基于碳水化合物的小分子对其蛋白质靶点的亲和力。尽管这种方法在增强与分离的碳水化合物结合蛋白的结合方面非常成功，但预测在细胞试验中能提高生物活性的多价呈现方式仍然具有挑战性。在这项工作中，我们研究了线性分子支架，用于合成一种低价呈现的二价半乳糖苷，我们之前已将其鉴定为机会性真菌病原体与颊上皮细胞（BECs）黏附的抑制剂。黏附抑制试验表明，多价糖缀合物在初次接触上皮细胞时对阻断其与BECs的黏附更有效。有趣的是，与最初的先导化合物相比，当它与酵母细胞预孵育时似乎没有任何作用，最初的先导化合物会使黏附减少25%。在酵母细胞和BECs共同孵育的竞争试验中，多价糖缀合物以剂量依赖的方式抑制高达49%的黏附。化合物对酵母细胞和BECs的联合作用使其在竞争试验中对其与BECs黏附的抑制率超过60%。
