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

Sabrina Santarsia, Ana Sofia Grosso, Filipa Trovão, Jesús Jiménez-Barbero, Ana Luísa Carvalho, Cristina Nativi, Filipa Marcelo

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2030-2036
Number of pages7
JournalChemmedchem
Volume13
Issue number19
DOIs
Publication statusPublished - 8 Oct 2018

Fingerprint

Galectin 3
Molecular recognition
Antigens
Neoplasm Metastasis
Neoplasms
Calorimetry
X ray crystallography
X Ray Crystallography
Cell adhesion
Entropy
Titration
Thermodynamics
Cell Adhesion
Scaffolds
Conformations
Epitopes
Assays
Membrane Proteins
Adenocarcinoma
Nuclear magnetic resonance

Keywords

  • galectin-3
  • molecular recognition
  • NMR spectroscopy
  • tumor-associated carbohydrate antigens
  • X-ray crystallography

Cite this

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title = "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.",
keywords = "galectin-3, molecular recognition, NMR spectroscopy, tumor-associated carbohydrate antigens, X-ray crystallography",
author = "Sabrina Santarsia and Grosso, {Ana Sofia} and Filipa Trov{\~a}o and Jes{\'u}s Jim{\'e}nez-Barbero and Carvalho, {Ana Lu{\'i}sa} and Cristina Nativi and Filipa Marcelo",
note = "info:eu-repo/grantAgreement/FCT/5876/147258/PT# The authors acknowledge Fundacao para a Ciencia e Tecnologia (FCT) Portugal for the project UCIBIO funding UID/Multi/04378/2013 co-financed by FEDER (POCI-01-0145-FEDER-007728). The NMR spectrometers are part of the National NMR Network (PTNMR) and are partially supported by Infrastructure Project No. 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC). F.M. thanks the FCT for IF investigator project IF/00780/2015 and Prof. Eurico J. Cabrita for fruitful discussions. F.M. and C.N. acknowledge COST Action CM1407 for funding the short-term scientific mission of S.S. A.L.C. acknowledges the FCT for projects PTDC/BBB-BEP/0869/2014 and Prof. Maria Joao Romao for access to the Macromolecular Crystallography facilities in UCIBIO. The authors thank the European Synchrotron Radiation Facility and the Diamond Light Source (DLS) for provision of synchrotron radiation facilities and access to beamlines ID30B and I03, respectively. Access to DLS was - through proposal MX16609 financed by iNEXT, project number 653706, funded by the Horizon 2020 programme of the European Union. The authors also acknowledge Cecilia Bonifacio (BioLab of UCIBIO) for assistance with ITC measurements and the project FCT-ANR/BBB-MET/0023/2012 for the equipment. The authors acknowledge the assistance of MSc Ana Diniz, Dr. Benedita Pinheiro, and Dr. Marcia Correia for their kind advice in protein expression/purification, crystallization, and structure refinement, respectively.",
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Molecular Recognition of a Thomsen–Friedenreich Antigen Mimetic Targeting Human Galectin-3. / Santarsia, Sabrina; Grosso, Ana Sofia; Trovão, Filipa; Jiménez-Barbero, Jesús; Carvalho, Ana Luísa; Nativi, Cristina; Marcelo, Filipa.

In: Chemmedchem, Vol. 13, No. 19, 08.10.2018, p. 2030-2036.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Santarsia, Sabrina

AU - Grosso, Ana Sofia

AU - Trovão, Filipa

AU - Jiménez-Barbero, Jesús

AU - Carvalho, Ana Luísa

AU - Nativi, Cristina

AU - Marcelo, Filipa

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N2 - 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.

AB - 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.

KW - galectin-3

KW - molecular recognition

KW - NMR spectroscopy

KW - tumor-associated carbohydrate antigens

KW - X-ray crystallography

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