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Selective Inhibition of Bacterial Intramolecular Trans-Sialidases via a Multidisciplinary Computational/Experimental Approach

Project description

Targeted inhibitors against bacterial enzymes

Sialidases are enzymes that remove sugar molecules from the surface of cells. While humans have their own sialidases for normal processes, some gut bacteria make special versions that can contribute to disease. Certain intramolecular trans-sialidases (IT-sialidases) from Ruminococcus species are linked to inflammatory bowel disease and colorectal cancer. With the support of the Marie Skłodowska-Curie Actions programme, the SELECT-IT project aims to develop small molecules to block these harmful bacterial enzymes without interfering with human homologues. Insight into IT-sialidase function alongside computer modelling will help researchers establish a novel treatment for bacteria-associated gut disorders.

Objective

SELECT-IT aims to develop small molecules that specifically target bacterial intramolecular trans(IT)-sialidases. IT-sialidases from Ruminococcus species have been related to progression of inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Following elucidation of the yet unknown mechanisms of action of IT-sialidases, I will rationally design candidate inhibitors, synthesise and characterise them, and assess their binding modes, inhibition efficacy and target selectivity. Inspired by strategies previously successful for antiviral drugs like Tamiflu, SELECT-IT will modify existing molecules such as Siastatin B, DANA, and 2,7-anhydro-Neu5Ac, as starting points to develop candidates that selectively inhibits bacterial sialidases while sparing human ones. The inhibitors will undergo systematic refinement through computer simulation (molecular dynamics, QM/MM and metadynamics) and experimental techniques (biochemical assays and NMR spectroscopy) to ensure high specificity. SELECT-IT aims to develop targeted inhibitors for managing bacterial infections linked to IBD and CRC, contributing directly to the creation of new therapeutic options.

Fields of science (EuroSciVoc)

Keywords

Programme(s)

Topic(s)

Funding Scheme

HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

(opens in new window) HORIZON-MSCA-2024-PF-01

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Coordinator

UNIVERSITAT DE BARCELONA
Net EU contribution
€ 194 074,56
Address
GRAN VIA DE LES CORTS CATALANES 585
08007 Barcelona
Spain
Region
Este Cataluña Barcelona
Activity type
Higher or Secondary Education Establishments
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Total cost
No data

Partners (2)