Molecular Recognition of a Thomsen–Friedenreich Antigen Mimetic Targeting Human Galectin‐3

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.

Targeting Galectins With Glycomimetics

“…Both experimental procedures pointed out that the disaccharidic moiety is the key epitope for h Gal-3, while the unnatural scaffold is exposed to the solvent. Similar observations have been reported for the natural ligand TF, where the attached Thr does not participate in the binding event (Santarsia et al, 2018 ). The thermodynamic profile of the system indicate that there is a slight gain in terms of K D , which interestingly arises from a favorable entropic contribution (−0.9 kcal mol −1 ), while there is less enthalpy gain (−4.3 kcal mol −1 ) compared to the natural TF (–TΔS 7.75 kcal mol −1 ; ΔH − 12.6 kcal mol −1 ) (Yongye et al, 2012 ).…”

“… Structure of mimetics 20 (Zetterberg et al, 2018 ), 21 (Santarsia et al, 2018 ), and 25 – 29 (Dahlqvist et al, 2019 ). Structure of TF antigen and histo-blood group antigens H, B, and A of type II ( 22–24) .…”

“…Another promising disaccharide mimetic has been presented by Marcelo and co-workers. The authors focused on the interplay between h Gal-3 and the Thomsen-Friedenreich (TF) antigen to develop a mimetic capable of binding h Gal-3 and compete with the natural antigen (Santarsia et al, 2018 ). The TF antigen ( 20 ), also known as pancarcinoma-related antigen, is a disaccharide (Gal β 1 → 3GalNAc) that decorates glycoproteins located on the cell-surface through O-Ser/Thr linkages ( Figure 7 ).…”

“…This work is an exquisite example of how a simple modification of the chemical nature of the ligand can lead to a big change in the entropy-enthalpy compensation phenomenon without changing the binding epitope. Overall, mimetic 21 might be considered as a putative lead compound to interfere with the aberrant interaction of h Gal-3 and the TF antigen (Santarsia et al, 2018 ).…”

Profiling of Naturally Occurring Antibodies to the Thomsen-Friedenreich Antigen in Health and Cancer: The Diversity and Clinical Potential

“…We speculate that the TF antigen on the circulating cancer cell may be blocked by natural TF Abs, thus competing with Gal3 binding and protecting against cancer cell adhesion to endothelium and metastasis. Another possible approach is the use of TF antigen mimetics to interfere with the Gal-3-mediated cancer cell adhesion and metastasis [145].…”