Sobati Saeideh, Shakouri Amir, Edalati Mahdi, Mohammadnejad Daryoush, Parvan Reza, Masoumi Javad, Abdolalizadeh Jalal
Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Department of Biochemistry, Higher Education Institute of Rab-Rashid, Tabriz, Iran.
Adv Pharm Bull. 2020 Sep;10(4):502-511. doi: 10.34172/apb.2020.062. Epub 2020 Aug 9.
Proprotein convertase subtilisin/kexin type 9 (PCSK9), as a vital modulator of low-density lipoprotein cholesterol (LDL-C) , is raised in hepatocytes and released into plasma where it binds to LDL receptors (LDLR), leading to their cleavage. PCSK9 adheres to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR which is confirmed by crystallography. LDLR expression is adjusted at the transcriptional level through sterol regulatory element binding protein 2 (SREBP-2) and at the post translational stages, specifically through PCSK9, and the inducible degrader of the LDLR PCSK9 inhibition is an appealing new method for reducing the concentration of LDL-C. In this review the role of PCSK9 in lipid homeostasis was elucidated, the effect of PCSK9 on atherosclerosis was highlighted, and contemporary therapeutic techniques that focused on PCSK9 were summarized. Several restoration methods to inhibit PCSK9 have been proposed which concentrate on both extracellular and intracellular PCSK9, and they include blockage of PCSK9 production by using gene silencing agents and blockage of it's binding to LDLR through antibodies and inhibition of PCSK9 autocatalytic processes by tiny molecule inhibitors.
前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）作为低密度脂蛋白胆固醇（LDL-C）的重要调节因子，在肝细胞中产生并释放到血浆中，在血浆中它与低密度脂蛋白受体（LDLR）结合，导致其裂解。PCSK9与LDLR的表皮生长因子样重复序列A（EGF-A）结构域结合，这一点已通过晶体学得到证实。LDLR的表达在转录水平上通过固醇调节元件结合蛋白2（SREBP-2）进行调节，在翻译后阶段则特别是通过PCSK9进行调节，而PCSK9抑制LDLR的诱导性降解是降低LDL-C浓度的一种有吸引力的新方法。在本综述中，阐明了PCSK9在脂质稳态中的作用，强调了PCSK9对动脉粥样硬化的影响，并总结了针对PCSK9的当代治疗技术。已经提出了几种抑制PCSK9的恢复方法，这些方法集中在细胞外和细胞内的PCSK9上，包括使用基因沉默剂阻断PCSK9的产生、通过抗体阻断其与LDLR的结合以及通过小分子抑制剂抑制PCSK9的自催化过程。
