前蛋白枯草溶菌素转化酶9抑制剂的研究进展

Research advances in proprotein convertase subtilisin/kexin type 9 inhibitors

过去的几十年里,他汀类药物通过降低低密度脂蛋白（LDL-C）可有效降低心血管事件风险,尽管如此,对于严重高胆固醇血症（如家族性高胆固醇血症）患者及他汀不耐受患者的替代治疗或联合治疗,前蛋白枯草溶菌素转化酶9（PCSK9）抑制剂是一种新的已被证明能够进一步降低LDL-C 50%~70%并作为单药治疗或与他汀类药物联合治疗的药物.PCSK9抑制剂在药物开发、基因突变及其临床效果已迅速发展为成功的临床前和临床研究多阶段1-3临床试验已完成或正在进行的一个最新的很好的例子.本文综述了基因的发现为药物靶标识别药物的迅速发展及PCSK9抑制剂大型临床试验结果.

Reduction in low-density lipoprotein cholesterol （LDL-C）, mainly with statins, has decreased the risk of cardiovascular events over the last few decades.However, there are several patient populations that warrant further decrease in LDL-C by additional cholesterol-lowering therapy other than statins.Proprotein convertase subtilisin/kexin type 9 （PCSK9） inhibitors are a new class of drugs that have been shown to further decrease LDL-C by 50%-70% when administered as a monotherapy or on a background therapy with statins.Proprotein convertase subtilisin/kexin type 9 inhibitors are also an excellent example of drug development in which discovery of gene mutations and its clinical effects have rapidly progressed into successful preclinical and clinical studies with multiple Phases 1-3 clinical trials completed or ongoing to date.This review summarizes the rapid evolution of the drug from genetic discovery to identification of targets for the drugs, to animal and human testing, and to large clinical outcomes trials, followed by discussion on foreseeable challenges of PCSK9 inhibitors.