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Inhibitor-Mediated Programming of Glycoforms

Project description

Site-directed and controlled glycosyltransferase activity

Genes encode the recipes to produce proteins. However, post-translational glycosylation – addition of carbohydrates to proteins – modulates protein function. Similarly, glycans on cell surfaces are essential to cell function. The complexity and heterogeneity of glycans is challenging to replicate in a controlled fashion. The EIC-funded IMProGlyco project aims to develop and demonstrate a radically innovative approach to glycan synthesis – a functional equivalent of site-directed mutagenesis for proteins. The team will use modelling of glycan biosynthesis and its inhibition to then tailor the activity of glycosyltransferases in the cell and thereby produce proteins with desired ensembles of glycans. The approach will support the development of therapeutics and vaccines.

Objective

Site-directed mutagenesis revolutionised the study of proteins and enabled the development of protein-based therapeutics. Our long-term vision is to have equivalent impact through the precise manipulation of the glycans (carbohydrates) on cells and recombinant proteins that will enable the discovery and production of the next generation of therapies for cancer, neurodegeneration and other disease families. The glycans that are present on most proteins and cells have a substantial impact on their biological functions, yet the untemplated nature of their synthesis leads to inherent heterogeneity in both their structure and activity. This heterogeneity is very difficult to control, making it impossible to generate defined glycan ensembles with optimal activity using current technology. Here we present a radically new approach to the controlled manipulation of glycans that will be the functional equivalent of site-directed mutagenesis for manipulating proteins. We will use the delivery of computationally defined mixtures of enzyme-specific inhibitors to the site of glycan biosynthesis in the cell to tune the activity of glycosyltransferases. Our approach, termed Inhibitor-Mediated Programming of Glycoforms (IMProGlyco) will provide an effective strategy to manipulate the glycosylation machinery and thereby generate proteins with defined ensembles of glycans. It will enable the production of precision glycan engineered therapeutic proteins and vaccines. Moreover, shaping cellular glycan profiles will aid discovery science to uncover glycan functions and improve therapeutic cells, such as those used in Chimeric Antigen Receptors cell Therapy (CAR-T). Our technology will be adaptable and expandable into other cell types and organisms allowing glycan shaping in all areas of eukaryotic cell biology to enable new biotechnological applications and fundamental studies of biology.

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HORIZON-EIC - HORIZON EIC Grants

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Call for proposal

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(opens in new window) HORIZON-EIC-2024-PATHFINDEROPEN-01

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Coordinator

UNIVERSITY OF LEEDS
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 1 087 312,00
Address
WOODHOUSE LANE
LS2 9JT Leeds
United Kingdom

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Region
Yorkshire and the Humber West Yorkshire Leeds
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 1 087 312,00

Participants (6)

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