CD38 bound to hydrolysed cADPR analogue
Crystallography of a synthetic cADPR analogue bound to CD38 reveals more about the CD38 mechanism of ligand hydrolysis.
MChem, PhD, MRSC
- Based at the University of Bath
My research uses synthetic chemistry to design molecules that will help us study calcium signalling in human cells.
Cell signalling forms part of vital processes, including cell division, fertilization and cell death. It is often dysfunctional in diseases like cancer, diabetes and inflammation. I hope that improving our understanding of these processes will also lead to new treatments for human disease.
I’m currently working on analogues of NAADP (Nicotinic Acid Adenine Dinucleotide Phosphate) – the most potent calcium releasing second messenger known to date. A combination of multiple negatively charged phosphate groups and the nicotinic acid make it both difficult to synthesize and challenging to study in biological systems.
I’m also continuing projects on the other nucleotide second messengers, ADPR (Adenosine DiPhosphate Ribose) and cADPR (cyclic-ADPR) to study their role in calcium release and their formation by CD38.
The first total synthesis of cIDPR depicted on the front cover of The Journal of Organic Chemistry - this stable, synthetic second messenger analogue releases calcium from intracellular stores.
Designer small molecules to target calcium signalling.
Swarbrick JM. et al, (2015), Biochem Soc Trans, 43, 417 - 425
Cyclic adenosine 5'-diphosphate ribose analogs without a "southern" ribose inhibit ADP-ribosyl cyclase-hydrolase CD38.
Swarbrick JM. et al, (2014), J Med Chem, 57, 8517 - 8529
'Click cyclic ADP-ribose': a neutral second messenger mimic.
Swarbrick JM. et al, (2014), Chem Commun (Camb), 50, 2458 - 2461
Structure-activity relationship of adenosine 5'-diphosphoribose at the transient receptor potential melastatin 2 (TRPM2) channel: rational design of antagonists.
Moreau C. et al, (2013), J Med Chem, 56, 10079 - 10102
Nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated calcium signaling and arrhythmias in the heart evoked by β-adrenergic stimulation.
Nebel M. et al, (2013), J Biol Chem, 288, 16017 - 16030
CD38 Structure-Based Inhibitor Design Using the N1-Cyclic Inosine 5'-Diphosphate Ribose Template.
Moreau C. et al, (2013), PLoS One, 8
Total synthesis of a cyclic adenosine 5'-diphosphate ribose receptor agonist.
Swarbrick JM. and Potter BV., (2012), J Org Chem, 77, 4191 - 4197