Seidah Nabil G
Clinical Research Institute of Montreal, Laboratory of Biochemical Neuroendocrinology, 110 Pine Ave West, Montreal, QC, H2W 1R7 Canada.
Expert Opin Ther Targets. 2009 Jan;13(1):19-28. doi: 10.1517/14728220802600715.
Proprotein convertase subtilisin/kexin type 9 (PCSK9), which promotes degradation of hepatic low density lipoprotein receptor (LDLR), has a role in plasma cholesterol metabolism. Its gene is associated with the development of familial hypercholesterolemia. mRNA silencing or inhibition of PCSK9-induced degradation of LDLR may be used to treat this disease.
OBJECTIVE/METHODS: To summarize approaches proposed to reduce the levels of PCSK9 and/or its activity.
RESULTS/CONCLUSIONS: mRNA knockdown approaches include the use of antisense oligonucleotides either as soluble phosphorothioates or locked nucleic acids and lipidoid nanoparticles embedded with small interfering RNAs. Passive immunization is also an option. Other strategies include inhibition of the zymogen activation of proPCSK9, or the interaction of PCSK9 with the EGF-A domain of the LDLR. The N-terminal prosegment and the C-terminal Cys-His rich domain (CHRD), are alternative targets. Annexin A2 specifically binds the CHRD and inhibits PCSK9 function, and Annexin A2 peptide mimics could pave the way for the development of novel PCSK9-inhibitory compounds.
前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）可促进肝脏低密度脂蛋白受体（LDLR）的降解，在血浆胆固醇代谢中发挥作用。其基因与家族性高胆固醇血症的发生有关。PCSK9的mRNA沉默或对其诱导的LDLR降解的抑制作用可用于治疗该疾病。
目的/方法：总结已提出的降低PCSK9水平和/或其活性的方法。
结果/结论：mRNA敲低方法包括使用作为可溶性硫代磷酸酯或锁核酸的反义寡核苷酸以及包埋有小干扰RNA的类脂纳米颗粒。被动免疫也是一种选择。其他策略包括抑制前体PCSK9的酶原激活，或PCSK9与LDLR的EGF-A结构域的相互作用。N端前肽段和C端富含半胱氨酸-组氨酸的结构域（CHRD）是其他靶点。膜联蛋白A2特异性结合CHRD并抑制PCSK9功能，膜联蛋白A2肽模拟物可为新型PCSK9抑制化合物的开发铺平道路。
