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.
Direct Activation of NADPH Oxidase 2 by 2-Deoxyribose-1-Phosphate Triggers Nuclear Factor Kappa B-Dependent Angiogenesis.
Vara D. et al, (2018), Antioxid Redox Signal, 28, 110 - 130
Second messenger analogues highlight unexpected substrate sensitivity of CD38: total synthesis of the hybrid "L-cyclic inosine 5'-diphosphate ribose".
Watt JM. et al, (2017), Sci Rep, 7
2'-Deoxyadenosine 5'-diphosphoribose is an endogenous TRPM2 superagonist.
Fliegert R. et al, (2017), Nat Chem Biol, 13, 1036 - 1044
Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy.
Kyratsous NI. et al, (2017), Proc Natl Acad Sci U S A, 114, E6381 - E6389
Ligand-induced activation of human TRPM2 requires the terminal ribose of ADPR and involves Arg1433 and Tyr1349.
Fliegert R. et al, (2017), Biochem J, 474, 2159 - 2175
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