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Research Interests

Our team research interests can be divided into three interconnected projects with the same aim: solving how glycocode is created and how it is read and translated by glycan-binding proteins.

01

Mucin O-glycosylation:
Catalysis and Molecular Recognition

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How the mucin O-glycosylation (natural and tumour-associated) is created by key glycosyltransferases?

In this project we aim to 1) decode the structural features within the catalysis of GTs; 2) unveil the molecular recognition process of natural substrates/products and mimetics by GTs and 3) glycoengineered mucin O-glycodomains containing different tumour-associated glycans and densities for molecular recognition studies in project 2 and 3. Our work in this project provide structural insights for the rational design of inhibitors, to block tumour-glycome expression and tumour growth, and potentially deliver mucin-based structures able to interfere with the aberrant tumour-glycans/immune-related lectins interactions or with interaction with pathogens. 

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Recent selected publications:

02

​Tumour-associated mucin O-glycans and their interaction with immune-related receptors

 

 

 

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Deciphering the molecular basis of how tumour-glycans/glycomimetics are read by immune related GBPs

In this project we aim to 1) decode the structural features that govern the recognition tumour-glycome recognition by immune-related GBPs; 2) structural-guided design of glycomimetics and/or glycopeptide mimetics targeting tumour-glycome/GBPs recognition to potentially alleviate anti-tumour suppressive immune responses and and/or metastasis; 3) rational design of tumour-glycans based vaccine(s) to induce the production of antibodies towards specific tumour-glycan antigens. Hence, using an integrated methodology that includes chemical synthesis, molecular biology, molecular modelling, and biophysical and structural-based techniques, with a particular focus on NMR-based binding methods we aim to characterize at the structural level natural tumour-associated glycans, glycomimetics and/or glycopeptide mimetics as well their interactions with different glycan-binding proteins (GBPs: lectins and antibodies). In the past years we have focused on human macrophage galactose C-type lectin (MGL), which recognize recognize N-acetylgalactosamine (α- or β- GalNAc) residues found in several tumour-glycans, in particular sialylated and non-sialylated form of Tn-epitopes in mucins. Galectin-3 was also a target of interested due to its involvement in the recognition of tumour-associated glycans. In addition, the molecular determinants that govern the recognition of tumour-associated mucin O-glycans by anti-glycan and anti-mucin antibodies has also been investigated. More recently, we have developed some research devoted to the immunoregulatory siglecs family of lectins, namely in siglec-7/9 and 15.    

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Selected publications:​

  • C. Oliveira Soares, A. S. Grosso, J. Ereño-Orbea, H. Coelho, F. Marcelo* "Molecular Recognition Insights of Sialic Acid Glycans by Distinct Receptors Unveiled by NMR and Molecular Modeling". Frontiers in Molecular Biosciences 8 (2021), Review, http://dx.doi. org/10.3389/fmolb.2021.727847. (corresponding author)

  • C. D. L. Lima, H. Coelho, A. Gimeno, F. Trovão, A. Diniz, J. S. Dias, J. Jiménez-Barbero, F. Corzana, A. L. Carvalho, E. J. Cabrita, F. Marcelo* "Structural Insights into the Molecular Recognition Mechanism of the Cancer and Pathogenic Epitope, LacdiNAc by Immune-Related Lectins". Chem - A Eur J. 2021;27:7951–7958. DOI: 10.1002/chem.202100800 (corresponding author)

  • A. Gabba, A. Bogucka, J. G. Luz, A. Diniz, H. Coelho, F. Corzana, F. Javier Cañada, F. Marcelo, P. V. Murphy, and G. Birrane* "Crystal Structure of the Carbohydrate Recognition Domain of the Human Macrophage Galactose C-Type Lectin Bound to GalNAc and the Tumor-Associated Tn Antigen". Biochemistry 60 17 (2021): 1327-1336. http://dx.doi.org/10.1021/acs.biochem.1c00009.

  • A. Diniz, H. Coelho, J. S. Dias, S. J. van Vliet, J. Jiménez-Barbero, F. Corzana, E. J. Cabrita, F. Marcelo* "The Plasticity of the Carbohydrate Recognition Domain Dictates the Exquisite Mechanism of Binding of Human Macrophage Galactose-Type Lectin". Chem. Eur. J. 25 61 (2019): 13945-13955. https://doi.org/10.1002/chem.201902780  (corresponding author)

  • J. Macías-León, I. A. Bermejo, A. Asín, A. García-García, I. Compañón, E. Jiménez-Moreno, H. Coelho, V. Mangini, I. S. Albuquerque, F. Marcelo, J. L. Asensio, G. J. L. Bernardes, H. J. Joshi, R. Fiammengo, O. Blixt, R. Hurtado-Guerrero* Francisco Corzana* "Structural characterization of an unprecedented lectin-like antitumoral anti-MUC1 antibody". Chemical Communications 56 96 (2020): 15137-15140. FRONT COVER http://dx.doi.org/10.1039/d0cc06349e

  • F. Marcelo, N. Supekar, F. Corzana, J. C. van der Horst, I. M. Vuist, D. Live, G.-Jan P.H. Boons, D. F. Smith S. J. van Vliet* "Identification of a secondary binding site in human macrophage galactose-type lectin by microarray studies: Implications for the molecular recognition of its ligands." J Biol Chem. 2019;294:1300–1311. DOI: 10.1074/jbc.RA118.004957

  • S. Santarsia, A. S. Grosso, F. Trovão, J. Jiménez-Barbero, A. Luísa Carvalho, C. Nativi*, F. Marcelo* "Molecular Recognition of a Thomsen-Friedenreich Antigen Mimetic Targeting Human Galectin-3". ChemMedChem 13 19 (2018): 2030-2036. http://dx.doi.org/10.1002/cmdc.201800525 (corresponding author)

  • A. Diniz; J. S. Dias; J. Jiménez-Barbero; F. Marcelo*; E. J. Cabrita*, "Protein-Glycan Quinary Interactions in Crowding Environment Unveiled by NMR Spectroscopy". Chem. Eur. J. 23 53 (2017): 13213-13220. HIGHLIGHTED AS HOT PAPER https://doi.org/10. 1002/chem.201702800. (corresponding author)

  • H. Coelho, T. Matsushita, G. Artigas, H. Hinou, F. J. Cañada, R. Lo-Man, C. LeClerc, E. J Cabrita, J. Jiménez-Barbero, S. Nishimura, F. Garcia-Martin*, F. Marcelo*. "The Quest for Anticancer Vaccines: Deciphering the Fine-Epitope Specificity of Cancer-Related Monoclonal Antibodies by Combining Microarray Screening and Saturation Transfer Difference NMR". J. Am. Chem. Soc. 137 39 (2015): 12438-12441. http://dx.doi.org/10.1021/jacs.5b06787 (corresponding author)

  • F. Marcelo*, F. Garcia-Martin, T. Matsushita, J. Sardinha, H. Coelho, A. Oude-Vrielink, C. Koller, S. André, E. J. Cabrita, H. Gabius, S. Nishimura, J. Jiménez-Barbero, F. J. Cañada*. "Delineating Binding Modes of Gal/GalNAc and Structural Elements of the Molecular Recognition of Tumor-Associated MucinGlycopeptides by the Human Macrophage Galactose-Type Lectin". Chem. Eur. J. 20 49 (2014): 16147-16155. HIGHLIGHTED AS VERY IMPORTANT PAPER  http://dx.doi.org/10.1002/chem.201404566 (corresponding author)

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03

Mucin O-glycans and Bacteria Crosstalk in infection and cancer

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Towards structural elucidation of mucin O-glycosylation (catalysis) and recognition (GBPs binding) using a combined NMR and molecular modelling toolbox

Mucin O-glycan domains are major components of the gastrointestinal tract, and they act as recognition sites for adhesive GBPs of commensal and pathogenic bacteria. While mucin O-glycans act as a protective barrier against pathogens, some pathogenic bacterial strains (e.g. Salmonella) use them as contact points for adherence and invasion processes. Identification and structural characterization of the mucin O-glycans that participate in the adhesion and recognition process of bacterial GBPs, together with the elucidation of the mucin O-glycans/bacterial GBPs molecular complexes (including the characterization of the cellular substructure of the bacterial GBPs in the presence and absence of mucin O-glycans) are essential to understand infection mechanisms and to comprehend whether tumour-associated mucin O-glycans are bound to bacterial GBPs and if such interactions contribute to cancer progression.

This is the latest research line and was recognized with a CEEC contract on this topic (2020.03261.CEECIND, title “Picturing pathogen infection: A structure-functional approach to interrogate host-glycans/Salmonella crosstalk” - Dr. H. Coelho) and an exploratory grant (Reference: EXPL/QUI-OUT/0069/2021; title “Interrogating Salmonella/host-glycans crosstalk: Structure functional approach.” Dr. H. Coelho (PI) and Dr. Filipa Marcelo (CO-PI)).

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