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

DOI: 10.1002/cmdc.201800525

Authors: Sabrina Santarsia (Univerity of Florence) , Ana Sofia Grosso (UCIBIO, Universidade Nova de Lisboa) , Filipa Trovão (UCIBIO, Universidade Nova de Lisboa) , Jesús Jiménez-Barbero (CIC-bioGUNE Bizkaia; Ikerbasque) , Ana Luisa Carvalho (UCIBIO, Universidade Nova de Lisboa) , Cristina Nativi (Univerity of Florence) , Filipa Marcelo (Universidade Nova de Lisboa)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemmedchem

State: Published (Approved)
Published: August 2018
Diamond Proposal Number(s): 16609

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.

Journal Keywords: Molecular Recognition; Tumour-associated carbohydrate antigens; Galectin-3; NMR Spectroscopy; X-Ray Crystallography

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography

Other Facilities: ESRF

Added On: 16/08/2018 14:47

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)