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Galectin-8N terminal domain in complex with Methyl 3-O-[3-O-benzyloxy]-malonyl-beta-D-galactopyranosideGalectin-8N terminal domain in complex with Methyl 3-O-[3-O-benzyloxy]-malonyl-beta-D-galactopyranoside
Structural highlights
Function[LEG8_HUMAN] Lectin with a marked preference for 3'-O-sialylated and 3'-O-sulfated glycans.[1] Publication Abstract from PubMedGalectin-8 is a beta-galactoside recognising protein having an important role in the regulation of bone remodeling, cancer progression and metastasis. Methyl-beta-D-galactopyranoside malonyl aromatic esters have been designed to target and engage with particular amino acid residues of the galectin-8N extended carbohydrate-binding site. The chemically synthesized compounds had in vitro binding affinity towards galectin-8N in the range of 5-33 muM, 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 SUM159 breast cancer cell line. X-ray crystallographic structure determination revealed that these monosaccharide-based compounds bind galectin-8N by engaging its unique arginine (Arg59), and simultaneously cross-linking to another (Arg45) located across the carbohydrate-binding site. This structure-based drug design approach has led to discovery of novel monosaccharide galactose-based antagonists, with the strongest binding compound (Kd 5.72 microM) being 7-fold tighter than the disaccharide lactose. Rational design and synthesis of methyl-beta-D-galactomalonyl phenyl esters as potent galectin-8N antagonists.,Patel B, Kishor C, Houston TA, Shatz-Azoulay H, Zick Y, Vinik Y, Blanchard H J Med Chem. 2020 Aug 18. doi: 10.1021/acs.jmedchem.0c00602. PMID:32809817[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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