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1.
Chem Sci ; 11(47): 12662-12670, 2020 Oct 21.
Article in English | MEDLINE | ID: mdl-34094460

ABSTRACT

Two orthogonal, metal free click reactions, enabled to glycosylate ubiquitin and its mutant A28C forming two protein scaffolds with high affinity for BambL, a lectin from the human pathogen Burkholderia ambifaria. A new fucoside analogue, with high affinity with BambL, firstly synthetized and co-crystallized with the protein target, provided the insights for sugar determinants grafting onto ubiquitin. Three ubiquitin-based glycosides were thus assembled. Fuc-Ub, presented several copies of the fucoside analogue, with proper geometry for multivalent effect; Rha-A28C, displayed one thio-rhamnose, known for its ability to tuning the immunological response; finally, Fuc-Rha-A28C, included both multiple fucoside analogs and the rhamnose residue. Fuc-Ub and Fuc-Rha-A28C ligands proved high affinity for BambL and unprecedented immune modulatory properties towards macrophages activation.

2.
ChemMedChem ; 13(19): 2030-2036, 2018 10 08.
Article in English | MEDLINE | ID: mdl-30094951

ABSTRACT

Overexpression of the Thomsen-Friedenreich (TF) antigen in cell membrane proteins occurs in 90 % of adenocarcinomas. Additionally, the binding of the TF antigen to human galectin-3 (Gal-3), also frequently overexpressed in malignancy, promotes cancer progression and metastasis. In this context, structures that interfere with this specific interaction have the potential to prevent cancer metastasis. A multidisciplinary approach combining the optimized synthesis of a TF antigen mimetic with NMR, X-ray crystallography methods, and isothermal titration calorimetry assays was used to unravel the molecular structural details that govern the Gal-3/TF mimetic interaction. The TF mimetic has a binding affinity for Gal-3 similar to that of the TF natural antigen and retains the binding epitope and bioactive conformation observed for the native antigen. Furthermore, from a thermodynamic perspective, a decrease in the enthalpic contribution was observed for the Gal-3/TF mimetic complex; however, this behavior is compensated by a favorable gain in entropy. From a structural perspective, these results establish our TF mimetic as a scaffold to design multivalent solutions to potentially interfere with Gal-3 aberrant interactions and for likely use in hampering Gal-3-mediated cancer cell adhesion and metastasis.


Subject(s)
Biomimetic Materials/metabolism , Disaccharides/metabolism , Galectin 3/metabolism , Pyridones/metabolism , Antigens, Tumor-Associated, Carbohydrate/chemistry , Binding Sites , Biomimetic Materials/chemical synthesis , Biomimetic Materials/chemistry , Blood Proteins , Crystallography, X-Ray , Disaccharides/chemical synthesis , Disaccharides/chemistry , Galectin 3/chemistry , Galectins , Humans , Protein Binding , Pyridones/chemical synthesis , Pyridones/chemistry , Thermodynamics
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