Rational design of glycan-based drugs for inflammatory disease

Lead Research Organisation: University of Manchester
Department Name: School of Biological Sciences

Abstract

This multidisciplinary PhD project is aimed at developing novel structural/biophysical/computational approaches for drug screening and discovery through a collaboration between Tony Day and Caroline Milner at the University of Manchester and Charles Blundell, Chief Scientific Officer at C4X Discovery. The research will build upon the expertise of the academic/industrial supervisors in NMR spectroscopy, biophysics and functional analysis focusing on a particular protein-glycan interaction as a tractable model system; namely the interaction of the polysaccharide hyaluronan (HA) with the HA-binding proteins CD44 and TSG-6, for which extensive structural/functional information is available. CD44 is a cell surface receptor that, by binding to HA, mediates the migration of T lymphocytes and many types of tumour cells into tissues, thereby contributing to inflammation (e.g. in arthritis and diabetes) and the metastatic spread of cancer. TSG-6 is a secreted protein associated with inflammatory conditions and in most cases is believed to help protect tissues from the damaging effects of inflammation. However, TSG-6 has also been associated with promoting airway hyper-responsiveness during asthma; here TSG-6 acts as a transferase that leads to a covalent modification of HA that contributes to lung pathology. The aim of this project is to develop specific and differentiated inhibitors that block HA binding to CD44 and TSG-6, creating compounds that would be very valuable in understanding the biology of these important proteins and have potential as anti-inflammatory drugs. The project will serve as an excellent training for those interested in pursuing a scientific career in either the academic or pharmaceutical sectors.

Supporting references:
Nagy N, Kaber G, Johnson PY, Gebe JA, Preisinger A, Falk BA, Gupta V, Gooden MD, Vernon RB, Bogdani M, Kulpers HF, Day AJ, Campbell DJ, Wight TN & Bollyky PL Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis. (2015) J. Clin. Invest. 125, 3928-3940. Front cover & Editor's pick.
Georgsson J, Bergström F, Nordqvist A, Watson MJ, Blundell CD, Johansson MJ, Petersson AU, Yuan ZQ, Zhou Y, Kristensson L, Kakol-Palm D, Tyrchan C, Wellner E, Bauer U, Brodin P, & Henriksson AS. GPR103 antagonists demonstrating anorexigenic activity in vivo: design and development of pyrrolo[2,3-c]pyridines that mimic the C-terminal Arg-Phe motif of QRFP26. (2015) J. Med. Chem. 57, 5935-5948.
Higman VA, Briggs DC, Mahoney DJ, Blundell CD, Sattelle B, Dyer D, Green DE, DeAngelis PL, Almond A, Milner CM & Day AJ. A refined model for the TSG-6 Link module in complex with hyaluronan: use of defined oligosaccharides to probe structure and function. (2014) J. Biol. Chem., 289, 5619-5634.
Blundell CD, Packer MJ & Almond A. Quantification of free ligand conformational preference by NMR and their relationship to the bioactive conformation. (2013) Bioorg. Med. Chem. 21, 4976-4987.
Banerji S, Wright AJ, Noble M, Mahoney DJ, Campbell ID, Day AJ & Jackson DG. Structures of the CD44-hyaluronan complex and new insight into a fundamental carbohydrate-protein interaction. (2007) Nat. Struct. Mol. Biol. 14, 234-239.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011208/1 01/10/2015 30/09/2023
1792538 Studentship BB/M011208/1 01/10/2016 30/09/2020 Rebecca Dodd
 
Description We have created a library of modified hyaluronan (HA) oligosaccharides that contain different chemical moieties and are a range of different lengths.
Interactions between Link_TSG6 (a target HA binding protein) and the library of modified oligosaccharides have been studied using isothermal titration calorimetry (ITC) and two-dimensional nuclear magnetic resonance (NMR) spectroscopy.
A new CD44 HA-binding domain (CD44_HABD) construct has been designed. Analyses are on-going to screen interactions of the library of modified oligosaccharides and CD44_HABD.
We are continuing to expand the library of modified oligosaccharides, using in silico analyses of modified oligosaccharides bound within the HA-binding sites of Link_TSG6 and CD44_HABD to facilitate rational design of additional HA modifications
Exploitation Route With further development, modified HA oligosaccharides could be used as reagents in HA research (e.g. as 'tool compounds') and may also have potential as anti-inflammatory and anti-metastatic drugs.
Sectors Pharmaceuticals and Medical Biotechnology

 
Description The research project is allowing C4X Discovery, a small molecule pharmaceutical company, to work with larger molecules (i.e. glycans, between 700 Da and 2000 Da) and test their software systems and experimental procedures on a tractable model system of hyaluronan and hyaluronan binding proteins.
First Year Of Impact 2018
Sector Pharmaceuticals and Medical Biotechnology
 
Description Pint of Science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Events arranged across three days to bring academic research to the general public in an informal setting. Talks raised questions from the audience.
Year(s) Of Engagement Activity 2018
 
Description WTCCMR Science - Art Masterclasses at The Whitworth Art Gallery with Sally Gilford 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Children from local primary schools attended the Art Gallery for a workshop run by Sally Gilford, looking at patterns in art and how scientists look for patterns in data. Childrens views on 'what is a scientist' were discussed.
Year(s) Of Engagement Activity 2016,2017
URL https://www.wellcome-matrix.org/news/centre-news67/