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首页> 外文期刊>Biochemical Pharmacology >Interaction of a small molecule Natura-alpha and STAT3-SH2 domain to block Y705 phosphorylation and inhibit lupus nephritis
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Interaction of a small molecule Natura-alpha and STAT3-SH2 domain to block Y705 phosphorylation and inhibit lupus nephritis

机译：小分子 Natura-α 和 STAT3-SH2 结构域的相互作用以阻断 Y705 磷酸化并抑制狼疮性肾炎

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A small molecule, Natura-alpha, a clinical stage investigational new drug for certain inflammatory diseases, has been evaluated for drug interaction with STAT3 and inhibiting systemic lupus erythematosus (SLE). Studies have revealed that it selectively inhibits STAT3-Y705 phosphorylation and, suppresses pro inflammatory cytokines, stimulates anti-inflammatory cytokine IL-10, thereby skewing T cell differentiation from the Th1/Th17 lineages toward the Treg lineage. The potential binding of the drug to STAT3 protein has been investigated with a computational modeling and docking simulation using X-ray crystal structure of the STAT3 3 homodimer. Natura-alpha was shown to directly bind to SH2 domain of STAT3 and forms H-bonds with amino acids Glu594 and Arg609. The phosphorylation of Y705 was prevented and making the formation of STAT3 homodimer impossible, thereby blocking STAT3 activation. The in vivo efficacy of Natura-alpha in SLE was evaluated in a bioassay with NZB/W female mice. Mice at week 19 were given orally Natura-alpha at 25 or 75 mg/kg, once a day, 5 days per week for 29 weeks. Mice were monitored weekly until 52 weeks of age. Both dosages were effective to reduce proteinuria and significantly improved animal survival rate. The renal functions were preserved with glomerular lesions reversed, which paralleled with decreased C3 deposit. The numbers of kidney cells stained with phosphorylated STAT3-Y705 remarkably decreased, demonstrating blocking of Y-705 phosphorylation by the treatment. Since NZB/W mice develop nephritis which resembles SLE in men, the data strongly suggests that Natura-alpha may be a potential effective therapeutic agent for lupus. (C) 2015 Elsevier Inc. All rights reserved.
机译：一种小分子 Natura-alpha 是一种针对某些炎症性疾病的临床阶段研究性新药，已经评估了与 STAT3 的药物相互作用和抑制系统性红斑狼疮 （SLE） 的药物相互作用。研究表明，它选择性地抑制 STAT3-Y705 磷酸化，抑制促炎细胞因子，刺激抗炎细胞因子 IL-10，从而使 T 细胞从 Th1/Th17 谱系向 Treg 谱系分化。使用 STAT3 [3 同源二聚体的 X 射线晶体结构，通过计算建模和对接模拟研究了药物与 STAT3 蛋白的潜在结合。Natura-alpha 被证明直接与 STAT3 的 SH2 结构域结合，并与氨基酸 Glu594 和 Arg609 形成氢键。Y705 的磷酸化被阻止，使 STAT3 同型二聚体的形成变得不可能，从而阻断了 STAT3 的激活。在 NZB/W 雌性小鼠的生物测定中评估了 Natura-α 在 SLE 中的体内疗效。第19周的小鼠口服Natura-α，剂量为25或75mg / kg，每天一次，每周5天，持续29周。每周监测小鼠，直到52周龄。两种剂量均有效减少蛋白尿，显著提高动物存活率。肾功能得以保留，肾小球病变逆转，这与C3沉积物减少平行。用磷酸化 STAT3-Y705 染色的肾细胞数量显着减少，表明该治疗阻断了 Y-705 磷酸化。由于NZB / W小鼠在男性中出现类似于SLE的肾炎，因此数据强烈表明Natura-α可能是狼疮的潜在有效治疗剂。（C） 2015 爱思唯尔公司保留所有权利。

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