Institute for Glycomics, Griffith University, Gold Coast Campus, Southport, Queensland 4222, Australia.
School of Chemistry and Molecular Bioscience, and Molecular Horizons, University of Wollongong, Wollongong, New South Wales 2522, Australia.
J Med Chem. 2020 Oct 22;63(20):11573-11584. doi: 10.1021/acs.jmedchem.0c00602. Epub 2020 Oct 1.
Galectin-8 is a β-galactoside-recognizing protein having an important role in the regulation of bone remodeling and cancer progression and metastasis. Methyl β-d-galactopyranoside malonyl aromatic esters have been designed to target and engage with particular amino acid residues of the galectin-8 extended carbohydrate-binding site. The chemically synthesized compounds had binding affinity toward galectin-8 in the range of 5-33 μM, as evaluated by isothermal titration calorimetry. This affinity directly correlated with the compounds' ability to inhibit galectin-8-induced expression of chemokines and proinflammatory cytokines in the SUM159 breast cancer cell line. X-ray crystallographic structure determination revealed that these monosaccharide-based compounds bind galectin-8 by engaging its unique arginine (Arg59) and simultaneously cross-linking to another arginine (Arg45) located across the carbohydrate-binding site. This structure-based drug design approach has led to the discovery of novel monosaccharide galactose-based antagonists, with the strongest-binding compound ( 5.72 μM) holding 7-fold tighter than the disaccharide lactose.
半乳凝集素-8 是一种β-半乳糖苷识别蛋白，在调节骨重塑和癌症的进展和转移方面具有重要作用。已经设计了甲基β-d-半乳糖吡喃糖苷丙二酰芳香酯，以靶向并与半乳凝集素-8 扩展的碳水化合物结合位点的特定氨基酸残基结合。通过等温滴定量热法评估，这些化学合成的化合物对半乳凝集素-8 的结合亲和力在 5-33 μM 范围内。这种亲和力与化合物抑制半乳凝集素-8 诱导 SUM159 乳腺癌细胞系中趋化因子和促炎细胞因子表达的能力直接相关。X 射线晶体结构测定表明，这些基于单糖的化合物通过与半乳凝集素-8 的独特精氨酸（Arg59）结合，并同时与位于碳水化合物结合位点对面的另一个精氨酸（Arg45）交联，从而结合半乳凝集素-8。这种基于结构的药物设计方法导致发现了新型单糖半乳糖基拮抗剂，其中结合最强的化合物（5.72 μM）比二糖乳糖结合得紧密 7 倍。
