当前位置: X-MOL 学术Annu. Rev. Pharmacol. Toxicol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
PCSK9: Regulation and Target for Drug Development for Dyslipidemia
Annual Review of Pharmacology and Toxicology ( IF 12.5 ) Pub Date : 2017-01-06 00:00:00 , DOI: 10.1146/annurev-pharmtox-010716-104944
Amy C. Burke 1 , Jacqueline S. Dron 1 , Robert A. Hegele 1, 2 , Murray W. Huff 1, 2
Affiliation  

Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.

中文翻译:


PCSK9:血脂异常药物开发的法规和目标

原蛋白转化酶枯草杆菌蛋白酶/ kexin 9型(PCSK9)是一种分泌的酶原,主要在肝脏中表达。PCSK9在血浆中循环,与细胞表面低密度脂蛋白(LDL)受体结合,被内化,然后将该受体靶向溶酶体降解。天然存在的PCSK9的研究导致极端血浆LDL胆固醇(LDL-C)变异和动脉粥样硬化风险改变的基因变异,引发了生物学和药理学研究的洪流。在理解PCSK9的生理调节方面的快速进展很快被转化为可商业购买的PCSK9生物抑制剂,这些抑制剂可降低LDL-C水平并可能降低心血管疾病的预后。在这里,我们回顾了PCSK9从新基因到药物靶标,动物和人类测试以及最终到结果试验和临床应用的迅速发展。此外,我们探索了PCSK9抑制剂开发的遗传学指导路径如何举例说明药理学的新范例。最后,随着临床中PCSK9抑制作用的建立,我们考虑了一些潜在的挑战。

更新日期:2017-01-06
down
wechat
bug