Institute of nuclear sciences Vinca, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Belgrade, Serbia.
Medical Faculty in Novi Sad, Clinical Center of Vojvodina, Novi Sad, Serbia.
Curr Drug Targets. 2018;19(9):1058-1067. doi: 10.2174/1389450119666171205101401.
Despite the intensive research and progress in modern pharmacotherapy, hypercholesterolemia and related cardiovascular complications remain one of the leading causes of mortality and disability in the modern world. A significant contribution to the treatment of hypercholesterolemia was made by the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9). This enzyme is responsible for the degradation of the low-density lipoprotein (LDL) receptor (LDLR) found at the surface of the plasma membrane in the liver and directly associated with serum LDL level. Limitations in standard therapy used in the treatment of lipid disorders have led to the development of new drugs, such as an inhibitor of PCSK9. Over the past years, the greatest achievement in discovering the PCSK9 inhibitor was made by designing monoclonal antibodies that disable PCSK9 to bind LDLR and RNA interference to reduce PCSK9 production, but one of the main disadvantages is costeffectiveness. In this review, we will summarize the most recent findings of basic and clinical studies which focus on PCSK9 function, regulation and therapeutic target for the treatment of hypercholesterolemia and associated cardiovascular diseases.
尽管在现代药物治疗方面进行了深入的研究和进展，但高胆固醇血症和相关心血管并发症仍然是现代世界导致死亡和残疾的主要原因之一。前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9（PCSK9）的发现为高胆固醇血症的治疗做出了重大贡献。这种酶负责降解肝脏质膜表面发现的低密度脂蛋白（LDL）受体（LDLR），并与血清 LDL 水平直接相关。在治疗脂质紊乱的标准治疗中存在局限性，导致了新药物的开发，如 PCSK9 抑制剂。在过去的几年中，发现 PCSK9 抑制剂的最大成就是设计了能够使 PCSK9 无法与 LDLR 结合的单克隆抗体和降低 PCSK9 产生的 RNA 干扰，但主要缺点之一是成本效益。在这篇综述中，我们将总结基础和临床研究的最新发现，这些研究集中在 PCSK9 的功能、调节和治疗靶点上，以治疗高胆固醇血症和相关心血管疾病。
