Nat Commun:GSK3008348:肺纤维化的下一个良药?

2020-09-18 xiaozeng MedSci原创

纤维化是多种疾病发病和致死的主要原因。受伤或长期炎症反应后伤口的异常愈合会导致纤维化的发生。特发性肺纤维化(IPF)是特发性间质性肺炎中最常见的疾病,IPF的药理学治疗手段有限,目前国际上批准的药物吡

纤维化是多种疾病发病和致死的主要原因。受伤或长期炎症反应后伤口的异常愈合会导致纤维化的发生。特发性肺纤维化(IPF)是特发性间质性肺炎中最常见的疾病,IPF的药理学治疗手段有限,目前国际上批准的药物吡非尼酮(pirfenidone)和尼达尼布(nintedanib)仅能延缓IPF的发展,而并不能阻止或逆转病程。

整合素αvβ6在促纤维化调控因子TGF-β的激活过程中起着至关重要的作用。既往研究显示,IPF患者中的αvβ6的表达水平上调,说明该整合素不仅可作为潜在生物标志物,而且还可能是潜在的治疗靶标。

GSK3008348的结构、溶解度和药代动力学特性

该研究鉴定了一种临床候选药物:GSK3008348,是一种选择性小分子αvβ6 RGD模拟物,并通过一系列疾病相关临床前实验分析该药物的效果。研究人员发现,在人IPF肺中GSK3008348与αvβ6具有高亲和力,并能够降低下游促纤维化TGF-β信号至正常水平。

GSK3008348治疗对肺部胶原的影响

在肺上皮细胞中,GSK3008348可诱导整合素αvβ6的快速内化和溶酶体途径降解。在博来霉素诱导肺纤维化模型中,GSK3008348通过结合αvβ6,对TGFβ信号转导通路进行长期抑制作用,并减少肺部胶原沉积和血清中C3M(IPF相关标志物)的水平。


综上,该研究结果揭示了GSK3008348或可成为纤维化疾病的一个潜在治疗药物。

 

原始出处:

John, A.E., Graves, R.H., Pun, K.T. et al. Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis. Nat Commun 11, 4659 (16 September 2020).

 

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    2021-04-29 liuli5079
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    2021-05-30 anminleiryan
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    2021-08-18 liye789132251
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    2020-09-19 小惠

    超级好的好文章

    0

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