Molecular recognition of a Thomsen-Friedenreich antigen mimetic targeting human galectin-3

Citation:
Santarsia, Sabrina, Ana Sofia Grosso, Filipa Trovão, Jesús Jiménez-Barbero, Ana Luísa Carvalho, Cristina Nativi, and Filipa Marcelo. "Molecular recognition of a Thomsen-Friedenreich antigen mimetic targeting human galectin-3." ChemMedChem. Aug 9. doi: 10.1002/cmdc.201800525. [Epub ahead of print] (2018).

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 display the potential to prevent cancer metastasis. Herein, a multidisciplinary approach, combining the optimized synthesis of a TF-antigen mimetic with NMR, X-ray crystallography methods and isothermal titration calorimetry assays has been employed to unravel the molecular structural details that govern the Gal-3/TF-mimetic interaction. The TF-mimetic presents a binding affinity for Gal-3 similar to the TF-natural antigen and retains the binding epitope and the 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 behaviour is compensated by a favourable entropy gain. 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 likely be used to hamper Gal-3-mediated cancer cells adhesion and metastasis.

Notes:

doi: 10.1002/cmdc.201800525

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