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Repurposing of Tranilast for Potential Neuropathic Pain Treatment by Inhibition of Sepiapterin Reductase in the BH4 Pathway
Version 2 2019-08-23, 18:36
Version 1 2019-07-10, 14:36
journal contribution
posted on 2019-08-23, 18:36 authored by Benjamin
J. R. Moore, Barira Islam, Sean Ward, Olivia Jackson, Rebecca Armitage, Jack Blackburn, Shozeb Haider, Patrick C. McHughTetrahydrobiopterin (BH4) is a cofactor in the production
of various signaling molecules including nitric oxide, dopamine, adrenaline,
and noradrenaline. BH4 levels are critical for processes
associated with cardiovascular function, inflammation, mood, pain,
and neurotransmission. Increasing pieces of evidence suggest that
BH4 is upregulated in chronic pain. Sepiapterin reductase
(SPR) catalyzes both the reversible reduction of sepiapterin to dihydrobiopterin
(BH2) and 6-pyruvoyl-tetrahydrobiopterin to BH4 within the BH4 pathway. Therefore, inhibition of SPR
by small molecules can be used to control BH4 production
and ultimately alleviate chronic pain. Here, we have used various
in silico and in vitro experiments to show that tranilast, licensed
for use in bronchial asthma, can inhibit sepiapterin reduction by
SPR. Docking and molecular dynamics simulations suggest that tranilast
can bind to human SPR (hSPR) at the same site as sepiapterin including
S157, one of the catalytic triad residues of hSPR. Colorimetric assays
revealed that tranilast was nearly twice as potent as the known hSPR
inhibitor, N-acetyl serotonin. Tranilast was able
to inhibit hSPR activity both intracellularly and extracellularly
in live cells. Triple quad mass spectrophotometry of cell lysates
showed a proportional decrease of BH4 in cells treated
with tranilast. Our results suggest that tranilast can act as a potent
hSPR inhibitor and therefore is a valid candidate for drug repurposing
in the treatment of chronic pain.