Unité Fonctionnalité et Ingénierie des Protéines (UFIP), CNRS, UMR 6286, Université de Nantes, Nantes, France.
Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia.
Chem Biol Drug Des. 2020 Oct;96(4):1123-1133. doi: 10.1111/cbdd.13683.
Galectins play key roles in numerous biological processes. Their mode of action depends on their localization which can be extracellular, cytoplasmic, or nuclear and is partly mediated through interactions with β-galactose containing glycans. Galectins have emerged as novel therapeutic targets notably for the treatment of inflammatory disorders and cancers. This has stimulated the design of carbohydrate-based inhibitors targeting the carbohydrate recognition domains (CRDs) of the galectins. Pursuing this approach, we reasoned that linear oligogalactosides obtained by straightforward iterative click chemistry could mimic poly-lactosamine motifs expressed at eukaryote cell surfaces which the extracellular form of galectin-3, a prominent member of the galectin family, specifically recognizes. Affinities toward galectin-3 consistently increased with the length of the representative oligogalactosides but without reaching that of oligo-lactosamines. Elucidation of the X-ray crystal structures of the galectin-3 CRD in complex with a synthesized di- and tri-galactoside confirmed that the compounds bind within the carbohydrate-binding site. The atomic structures revealed that binding interactions mainly occur with the galactose moiety at the non-reducing end, primarily with subsites C and D of the CRD, differing from oligo-lactosamine which bind more consistently across the whole groove formed by the five subsites (A-E) of the galectin-3 CRD.
半乳糖凝集素在许多生物过程中发挥着关键作用。它们的作用模式取决于其定位，定位可以是细胞外、细胞质或核内，部分通过与含有β-半乳糖的糖缀合物相互作用来介导。半乳糖凝集素已成为新的治疗靶点，特别是在治疗炎症性疾病和癌症方面。这刺激了基于碳水化合物的抑制剂的设计，这些抑制剂针对半乳糖凝集素的碳水化合物识别结构域（CRD）。基于这种方法，我们推断通过简单的迭代点击化学获得的线性寡半乳糖苷可以模拟在真核细胞表面表达的多乳糖胺基序，而半乳糖凝集素-3 的细胞外形式特别识别这些基序，半乳糖凝集素-3 是半乳糖凝集素家族的一个重要成员。代表寡半乳糖苷对半乳糖凝集素-3 的亲和力随着长度的增加而一致增加，但没有达到寡乳糖胺的亲和力。合成的二半乳糖苷和三半乳糖苷与半乳糖凝集素-3 CRD 的 X 射线晶体结构的阐明证实了这些化合物结合在碳水化合物结合位点内。原子结构表明，结合相互作用主要发生在非还原端的半乳糖部分，主要发生在 CRD 的 C 和 D 亚基上，与寡乳糖胺不同，寡乳糖胺更一致地结合在半乳糖凝集素-3 CRD 的五个亚基（A-E）形成的整个槽中。
