Department of Pharmacological Sciences, Università degli Studi di Milano, Italy.
Nutr Metab Cardiovasc Dis. 2011 Nov;21(11):835-43. doi: 10.1016/j.numecd.2011.06.002. Epub 2011 Sep 23.
This short review aims at summarizing the current information on Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) structure and function focusing also on the therapeutic possibilities based on the inhibition of this protein.
PCSK9 has been recently discovered as the third gene involved in autosomal dominant hypercholesterolemia. PCSK9 binds and favors degradation of the low-density lipoprotein receptor (LDLR) and thereby modulates the plasma levels of LDL-cholesterol (LDL-C). Some of the natural occurring PCSK9 mutations increase the protein function (gain of function) and cause hypercholesterolemia, whereas loss of function mutations associate with hypocholesterolemia. Since the loss of a functional PCSK9 in humans is not associated with apparent deleterious effects, this protease is an attractive target for the development of lowering plasma LDL-C agents, either alone or in combination with statins.
Inhibition of PCSK9 is emerging as a novel strategy for the treatment of hypercholesterolemia and data obtained from pre-clinical studies show that use of monoclonal antibodies, antisense oligonucleotides and short interfering RNA are effective in reducing LDL-C, clinical studies, accompanied by a better understanding of PCSK9 biology, are now necessary to address whether these new compounds will have a future in clinical practice.
本综述旨在总结目前关于脯氨酸内切酶枯草溶菌素/凝血酶 9（PCSK9）结构和功能的信息，重点介绍基于该蛋白抑制的治疗可能性。
PCSK9 最近被发现是常染色体显性高胆固醇血症的第三个相关基因。PCSK9 与 LDL 受体（LDLR）结合并促进其降解，从而调节 LDL 胆固醇（LDL-C）的血浆水平。一些天然存在的 PCSK9 突变增加了蛋白功能（获得功能）并导致高胆固醇血症，而功能丧失突变与低胆固醇血症相关。由于人类功能性 PCSK9 的缺失与明显的有害影响无关，因此该蛋白酶是开发降低血浆 LDL-C 药物的有吸引力的靶点，无论是单独使用还是与他汀类药物联合使用。
PCSK9 的抑制作为治疗高胆固醇血症的一种新策略正在出现，来自临床前研究的数据表明，使用单克隆抗体、反义寡核苷酸和短发夹 RNA 可有效降低 LDL-C，现在需要进行临床试验，同时更好地了解 PCSK9 生物学，以确定这些新化合物是否在临床实践中有未来。
