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Designer small molecules to target calcium signalling
Joanna M. Swarbrick, Andrew M. Riley,
Stephen J. Mills and Barry V.L. Potter
University of Bath, Bath, UK
Three nucleotide second messengers cADPR, NAADP and ADPR
are formed from NAD+ by the multifunctional cyclase CD38.
They mobilize Ca2+ using pathways unrelated to myo-inositol1,4,5-trisphosphate (IP3). Synthetic compounds addressing these
messengers open new avenues for exploring and manipulating
intracellular Ca2+-signalling and may lead to drug-like tools to
intervene in disease. Adenophostin is the most potent agonist at
the IP3-receptor (IP3R). Our analogues provide a binding model
for further design and development. Benzene polyphosphates
illustrate that a simple non-inositol template can be engineered to
give both IP3R agonists and antagonists. cADPR activates Ca2+
release via the ryanodine receptor. Using a chemoenzymatic or
total synthetic route cADPR can be selectively modified, giving
chemically and biologically stable tools to investigate structureactivity relationships (SAR), interfere with cADPR synthesis and
degradation and agonize/antagonize Ca2+ release. Analogues with
a synthetic pyrophosphate bioisostere inhibit cADPR hydrolysis
by CD38 and, surprisingly, retain the ability to release Ca2+,
suggesting a route to neutral and membrane-permeant tools.
Interestingly, preliminary results suggest smaller fragments also
exhibit weak activity. ADPR activates TRPM2 a Ca2+, Na+ and K+
permeable cation channel. Synthetic ADPR analogues provide
the first SAR for this emerging messenger, and a functional
antagonist. An analogue based on the NAADP nicotinic acid motif
antagonizes NAADP-mediated Ca2+ release and is effective in
vivo in heart arrhythmia and autoimmune disease, illustrating the
therapeutic potential of such small molecules.