摘要
背景:甲羟戊酸激酶缺乏症(MKD,OMIM#610377)是一种罕见的常染色体隐性代谢和炎症性疾病。 在MKD中,由于MVK基因的突变,甲羟戊酸激酶的缺陷功能导致甲羟戊酸衍生的中间体的短缺,这导致蛋白质的异戊烯化不平衡和甾醇的代谢改变。 这些缺陷导致复杂的多系统炎症和代谢综合征。 目的:虽然旨在阻断炎性细胞因子白细胞介素-1的生物疗法可以显着减少炎症,但它们cannot completely control the clinical 影响神经系统的症状。因此,MKD仍可被视为孤儿药。再现MKD-系统性炎症的MKD模型的可用性对于改善其发病机理的知识是至关重要的,这仍然是未知的。为了改善专利条件和生活质量,还需要新疗法。 方法:MKD细胞模型可通过生化抑制甲羟戊酸来源的类异戊二烯获得。值得注意的是,这些细胞对炎性刺激具有夸大的反应,可以通过用角鲨烯合酶的抑制剂萨拉哥酸处理来减少这种反应,从而增加酶促阻断剂上游的类异戊二烯中间体的可用性。 结果:醋酸lapaquistat(TAK-475,Takeda)可能获得类似的作用,这种药物10年前作为降胆固醇药进行了广泛的临床试验,具有良好的安全性。 结论:在这里,我们描述了支持可能将TAK-475从其最初预期用途重新定位到MKD治疗的临床前证据,并讨论其调节炎症性疾病中甲羟戊酸途径的潜力。
关键词: 胆固醇,他汀类药物,角鲨烯合成酶抑制剂,醋酸Lapaquistat,甲羟戊酸激酶缺乏症,高胆固醇血症,炎症。
Current Medicinal Chemistry
Title:Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice
Volume: 25 Issue: 24
关键词: 胆固醇,他汀类药物,角鲨烯合成酶抑制剂,醋酸Lapaquistat,甲羟戊酸激酶缺乏症,高胆固醇血症,炎症。
摘要: Background: Mevalonate Kinase Deficiency (MKD, OMIM #610377) is a rare autosomal recessive metabolic and inflammatory disease. In MKD, defective function of the enzyme mevalonate kinase, due to a mutation in the MVK gene, leads to the shortage of mevalonate- derived intermediates, which results in unbalanced prenylation of proteins and altered metabolism of sterols. These defects lead to a complex multisystem inflammatory and metabolic syndrome.
Objective: Although biologic therapies aimed at blocking the inflammatory cytokine interleukin- 1 can significantly reduce inflammation, they cannot completely control the clinical symptoms that affect the nervous system. For this reason, MKD can still be considered an orphan drug disease. The availability of MKD models reproducing the MKD-systematic inflammation, is crucial to improve the knowledge on its pathogenesis, which is still unknown. New therapies are also required in order to improve pateints’ conditions and their quality of life.
Methods: MKD-cellular models can be obtained by biochemical inhibition of mevalonatederived isoprenoids. Of note, these cells present an exaggerated response to inflammatory stimuli that can be reduced by treatment with zaragozic acid, an inhibitor of squalene synthase, thus increasing the availability of isoprenoids intermediates upstream the enzymatic block.
Results: A similar action might be obtained by lapaquistat acetate (TAK-475, Takeda), a drug that underwent extensive clinical trials as a cholesterol lowering agent 10 years ago, with a good safety profile.
Conclusions: Here we describe the preclinical evidence supporting the possible repositioning of TAK-475 from its originally intended use to the treatment of MKD and discuss its potential to modulate the mevalonate pathway in inflammatory diseases.
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Cite this article as:
Repositioning of Tak-475 In Mevalonate Kinase Disease: Translating Theory Into Practice, Current Medicinal Chemistry 2018; 25 (24) . https://dx.doi.org/10.2174/0929867324666170911161417
DOI https://dx.doi.org/10.2174/0929867324666170911161417 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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