Rational design of glycan-based drugs for inflammatory disease

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.