Dion Johann, Deshayes Frédérique, Storozhylova Nataliya, Advedissian Tamara, Lambert Annie, Viguier Mireille, Tellier Charles, Dussouy Christophe, Poirier Françoise, Grandjean Cyrille
Faculté des Sciences et des Techniques, Unité Fonctionnalité et Ingénierie des Protéines (UFIP), Université de Nantes, UMR CNRS 6286, 2 chemin de la Houssinière, B. P. 92208, 44322, Nantes Cedex 3, France.
Université Paris Diderot-Paris 7 Sorbonne Paris Cité, Institut Jacques Monod, UMR CNRS 7592, 15 rue Hélène Brion, 75205, Paris Cedex 13, France.
Chembiochem. 2017 Apr 18;18(8):782-789. doi: 10.1002/cbic.201600673. Epub 2017 Mar 22.
Galectins have been recognized as potential novel therapeutic targets for the numerous fundamental biological processes in which they are involved. Galectins are key players in homeostasis, and as such their expression and function are finely tuned in vivo. Thus, their modes of action are complex and remain largely unexplored, partly because of the lack of dedicated tools. We thus designed galectin inhibitors from a lactosamine core, functionalized at key C2 and C3' positions by aromatic substituents to ensure both high affinity and selectivity, and equipped with a spacer that can be modified on demand to further modulate their physico-chemical properties. As a proof-of-concept, galectin-3 was selectively targeted. The efficacy of the synthesized di-aromatic lactosamine tools was shown in cellular assays to modulate collective epithelial cell migration and to interfere with actin/cortactin localization.
半乳糖凝集素已被公认为是其参与的众多基本生物学过程的潜在新型治疗靶点。半乳糖凝集素是体内平衡的关键参与者，因此它们的表达和功能在体内得到精细调节。因此，它们的作用方式很复杂，在很大程度上仍未被探索，部分原因是缺乏专门的工具。因此，我们从乳糖胺核心设计了半乳糖凝集素抑制剂，通过芳族取代基在关键的C2和C3'位置进行功能化，以确保高亲和力和选择性，并配备了一个间隔基，可根据需要进行修饰以进一步调节其物理化学性质。作为概念验证，对半乳糖凝集素-3进行了选择性靶向。在细胞试验中表明，合成的二芳基乳糖胺工具可调节集体上皮细胞迁移并干扰肌动蛋白/皮层肌动蛋白的定位。
