This project aims to antagonize for the first time the superlectin BC2L-C from multi-drug resistant (MDR) pathogen Burkholderia cenocepacia. MDRs such as Burkholderia cenocepacia have become a hazard in the context of healthcareassociated infections, especially for patients admitted with cystic fibrosis or immunocompromising conditions. As other opportunistic Gram-negative bacteria, this pathogen establishes virulence and biofilms through lectin-mediated adhesion. In particular, the superlectin BC2L-C is believed to cross-link human epithelial cells to B. cenocepacia during pulmonary infection. With the ultimate goal of inhibiting the interactions between the N-terminal of BC2L-C and its target human oligosaccharides, we aim to design glycomimetic antagonists. Here we report the structural study of the target BC2L-C-N-terminal by X-ray crystallography, followed by the design and synthesis of a modular fucoside library of C- and N-glycomimetics. Lastly, we report the biophysical evaluation of the generated glycomimetics against BC2L-CNter by techniques such as STD-NMR, SPR, ITC, DSC; resulting in a lead structure with satisfactory affinity and two crystal structures of antagonist/lectin complexes.

DESIGN, SYNTHESIS AND EVALUATION OF ANTAGONISTS TOWARDS BC2L-C / R. Bermeo Malo ; tutor: A. VARROT; tutor: A. BERNARDI ; referee: C. NATIVI; referee: A. TITZ ; coordinator: E. Licandro. - Milano : Università degli studi di Milano. Dipartimento di Chimica, 2021 Jun 18. ((33. ciclo, Anno Accademico 2020.

DESIGN, SYNTHESIS AND EVALUATION OF ANTAGONISTS TOWARDS BC2L-C

BERMEO MALO, RAFAEL
2021-06-18

Abstract

This project aims to antagonize for the first time the superlectin BC2L-C from multi-drug resistant (MDR) pathogen Burkholderia cenocepacia. MDRs such as Burkholderia cenocepacia have become a hazard in the context of healthcareassociated infections, especially for patients admitted with cystic fibrosis or immunocompromising conditions. As other opportunistic Gram-negative bacteria, this pathogen establishes virulence and biofilms through lectin-mediated adhesion. In particular, the superlectin BC2L-C is believed to cross-link human epithelial cells to B. cenocepacia during pulmonary infection. With the ultimate goal of inhibiting the interactions between the N-terminal of BC2L-C and its target human oligosaccharides, we aim to design glycomimetic antagonists. Here we report the structural study of the target BC2L-C-N-terminal by X-ray crystallography, followed by the design and synthesis of a modular fucoside library of C- and N-glycomimetics. Lastly, we report the biophysical evaluation of the generated glycomimetics against BC2L-CNter by techniques such as STD-NMR, SPR, ITC, DSC; resulting in a lead structure with satisfactory affinity and two crystal structures of antagonist/lectin complexes.
BERNARDI, ANNA
LICANDRO, EMANUELA
Settore CHIM/06 - Chimica Organica
Settore BIO/10 - Biochimica
Settore BIO/11 - Biologia Molecolare
DESIGN, SYNTHESIS AND EVALUATION OF ANTAGONISTS TOWARDS BC2L-C / R. Bermeo Malo ; tutor: A. VARROT; tutor: A. BERNARDI ; referee: C. NATIVI; referee: A. TITZ ; coordinator: E. Licandro. - Milano : Università degli studi di Milano. Dipartimento di Chimica, 2021 Jun 18. ((33. ciclo, Anno Accademico 2020.
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/850474
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