SUGARSmart · Smart design of recombinant antibody fragments specific for carbohydrate molecules
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-07-10 → 2020-08-09
- EU contribution
- €175,866
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
SUGARSmart: Smart design of recombinant antibody fragments specific for carbohydrate molecules
Glycosylation is one of the most frequently used post-translational modifications (PTM), where proteins are altered with various glycan molecules. Such glycans are sometimes found only in particular groups, species, or organisms. For example, blood group antigens, Galα1,3Gal motif, and N-glycolylneuraminic acid (NeuGc) are not found in humans, and exposure to these non-self glycans can trigger severe allergic reactions in humans. Thus, it is essential to prevent the presence of any antigenic carbohydrate in biopharmaceuticals, and a majority of them are produced in animal cell lines. Therefore, it is crucial to design molecules that can be used to detect the presence of such antigenic carbohydrates in food or pharmaceuticals. Such biomolecules can be particular proteins called lectins, antibodies, and aptamers. The project “SUGARSmart” looks at the development of computational workflow to engineer glycan recognition molecules and enhance their binding affinity and specificity. The objective of this Marie Skłodowska Curie Action (MSCA) has been to (1) improve computational methodologies for modeling antibody-glycan recognition and (2) develop a computation workflow for the rational design of glycan recognition molecules. A parallel goal of this MSCA Fellowship is to foster the development of the researcher’s career in the glycosciences.
Data: CORDIS, © European Union
Project objective
The development of new approaches to explore the diverse role of glycans in normal and physio- pathological conditions of the cell is a major challenge. Our previous research recognized roles of anti-glycan recognition molecules (lectins and antibodies) in the diagnosis of diseases like cancer, immunity, and hyperacute rejection upon bioprosthetic transplantation etc. However, because of the structural complexity, well-established approaches for developing glycan-based therapeutics are limited.To address this issues, SUGARSmart aims to develop a workflow for rational design of single-chain fragment variable (scFv) antibodies to enhance glycan recognition capabilities, both specificity- and affinity-wise (improving detection limits of assays). Three major aims will be pursued: First, we will apply molecular modeling to predict mutations which lead to enhance affinity and specificity of anti-αGal scFv. A range of mutational strategies will be tested in order to learn which scFv domains, which particular locations (functionally important sites), and which mutations (aromatic or polar) are best suited to improve affinity and specificity. Second, computationally predicted mutants will be obtained by mutagenesis or chain shuffling. Validity of the predictions will be tested by affinity-measurement (ITC/SPR), array techniques and ELISA. At the end, validation of computational models of scFv-glycan interactions with experimental techniques will enable us to propose a workflow to engineer other anti-glycan scFv antibodies. Overall, this project proposes an interdisciplinary approach to enhance our ability to quantify and engineer glycan recognition molecules having potential application in the smart and tailored development of future diagnostic reagents and therapeutics. To the best of our knowledge this will be the first attempt to provide a complete and coherent framework for anti-glycan antibody engineering, combining a wide computational pipeline and experiments.
Original text from CORDIS.
Participants
- UNIVERSITY OF GALWAY · GalwayCoordinatorIreland
Links
Data: CORDIS, © European Union