Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D02027 (Tranilast)
 205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tetrahydrobiopterin (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.
ACS Omega 2019 Jul 31
PMID:Repurposing of Tranilast for Potential Neuropathic Pain Treatment by Inhibition of Sepiapterin Reductase in the BH4 Pathway. 3146 Mar 7

Traumatic brain injury (TBI) is a prevalent public healthcare concern frequently instigated by mechanical shock, traffic, or violence incidents, leading to permanent nerve damage, and there is no ideal treatment for it yet. In this study, a series of Rolipram-Tranilast hybrids were designed and synthesized. The neuroprotective activities of the Rolipram-Tranilast hybrids were evaluated both in vitro and in vivo. Compound 5 has been identified as the strongest neuroprotective molecule among the series with robust anti-oxidant and anti-inflammatory potentials. Compound 5 significantly increased the heme oxygenase-1 (HO-1) levels and the phosphorylated cAMP response elements binding protein (p-CREB) while it down-regulated phosphodiesterase-4 B (PDE4B) expression in vitro. Furthermore, compound 5 remarkably attenuated TBI and had a good safety profile in mice. Taken together, our findings suggested that compound 5 could serve as a novel promising lead compound in the treatment of TBI and other central nervous system (CNS) diseases associated with PDE4B and oxidative stress.
ACS Chem Neurosci 2020 08 05
PMID:Design, Synthesis, and Biological Evaluation of Novel Multifunctional Rolipram-Tranilast Hybrids As Potential Treatment for Traumatic Brain Injury. 3264 71