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首页> 外文期刊>ACS Omega >Repurposing of Tranilast for Potential Neuropathic Pain Treatment by Inhibition of Sepiapterin Reductase in the BH4 Pathway
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Repurposing of Tranilast for Potential Neuropathic Pain Treatment by Inhibition of Sepiapterin Reductase in the BH4 Pathway

机译：通过抑制SepHapterin还原酶在BH4途径中重新利用曲尼司特治疗潜在的神经性疼痛

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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.
机译：四氢生物蝶呤（BH4）是产生各种信号分子（包括一氧化氮，多巴胺，肾上腺素和去甲肾上腺素）的辅助因子。 BH4水平对于与心血管功能，炎症，情绪，疼痛和神经传递有关的过程至关重要。越来越多的证据表明，BH4在慢性疼痛中被上调。 Sepaapterin还原酶（SPR）催化BH4途径中sepiapterin可逆地还原为二氢生物蝶呤（BH2）和6-丙酮酰-四氢Biopterin还原为BH4。因此，小分子对SPR的抑制作用可用于控制BH4的产生并最终缓解慢性疼痛。在这里，我们已使用各种计算机模拟和体外实验来证明曲尼司特（已获准用于支气管哮喘）可以抑制SPR降低Sepaapterin的还原。对接和分子动力学模拟表明，曲尼司特可以与Sepaapterin包括S157（hSPR的催化三联残基之一）在同一位置结合人SPR（hSPR）。比色测定显示曲尼司特的功效几乎是已知的hSPR抑制剂N-乙酰羟色胺的两倍。 Tranilast能够在活细胞内和细胞外抑制hSPR活性。细胞裂解物的三重四极质谱法显示，曲尼司特处理的细胞中BH4呈比例下降。我们的结果表明曲尼司特可以作为有效的hSPR抑制剂，因此是治疗慢性疼痛的有效药物。

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