Department of Organic Chemistry, NCCR Chemical Biology, Faculty of Science, University of Geneva, Quai Ernest Ansermet 30, 1211, Geneva, Switzerland.
CERMAV UPR5301, CNRS, Université Grenoble Alpes, BP 53, 38041, Grenoble cedex 9, France.
Angew Chem Int Ed Engl. 2017 Jun 6;56(24):6762-6766. doi: 10.1002/anie.201700813. Epub 2017 May 15.
Pathogens frequently rely on lectins for adhesion and cellular entry into the host. Since these interactions typically result from multimeric binding of lectins to cell-surface glycans, novel therapeutic strategies are being developed with the use of glycomimetics as competitors of such interactions. Herein we study the benefit of nucleic acid based oligomeric assemblies with PNA-fucose conjugates. We demonstrate that the interactions of a lectin with epithelial cells can be inhibited with conjugates that do not form stable assemblies in solution but benefit from cooperativity between ligand-protein interactions and PNA hybridization to achieve high affinity. A dynamic dimeric assembly fully blocked the binding of the fucose-binding lectin BambL of Burkholderia ambifaria, a pathogenic bacterium, to epithelial cells with an efficiency of more than 700-fold compared to l-fucose.
病原体经常依赖凝集素来黏附和进入宿主细胞。由于这些相互作用通常是凝集素与细胞表面聚糖的多聚体结合引起的，因此正在开发使用糖模拟物作为这些相互作用的竞争者的新型治疗策略。在此，我们研究了基于核酸的寡聚体与 PNA-岩藻糖缀合物的结合带来的益处。我们证明，与上皮细胞的相互作用可以通过不形成溶液中稳定组装的缀合物来抑制，但受益于配体-蛋白质相互作用之间的协同作用和 PNA 杂交，从而实现高亲和力。与 l-岩藻糖相比，动态二聚体组装物完全阻止了致病细菌伯克霍尔德菌(Burkholderia ambifaria)的岩藻糖结合凝集素 BambL 与上皮细胞的结合，效率超过 700 倍。
