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Acta Pharmacologica Sinica (2017) 38: 301311 2017 CPS and SIMM All rights reserved 1671-4083/17 www.nature.com/aps
Review
Lowering serum lipids via PCSK9-targeting drugs: current advances and future perspectives
Ni-ya HE1, #, Qing LI1, #, Chun-yan WU1, #, Zhong REN1, Ya GAO1, Li-hong PAN1, Mei-mei WANG1, Hong-yan WEN2, Zhi-sheng JIANG1, Zhi-han TANG1, *, Lu-shan LIU1, *
1Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China; 2Medical College, Hunan University of Chinese Medicine, Changsha 410208, China
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9), also known as neural apoptosis regulated convertase (NARC1), is a key modulator of cholesterol metabolism. PCSK9 increases the serum concentration of low-density lipoprotein cholesterol by escorting low-density lipoprotein receptors (LDLRs) from the membrane of hepatic cells into lysosomes, where the LDLRs are degraded. Owing to the importance of PCSK9 in lipid metabolism, considerable effort has been made over the past decade in developing drugs targeting PCSK9 to lower serum lipid levels. Nevertheless, some problems and challenges remain. In this review we rst describesthe structure and function of PCSK9 and its gene polymorphisms. We then discuss the various designs of pharmacological targets of PCSK9, including those that block the binding of PCSK9 to hepatic LDLRs (mimetic peptides, adnectins, and monoclonal antibodies), inhibit PCSK9 expression (the clustered regularly interspaced short palindromic repeats/Cas9 platform, small molecules, antisense oligonucleotides, and small interfering RNAs), and interfere with PCSK9 secretion. Finally, this review highlights future challenges in this eld, including safety concerns associated with PCSK9 monoclonal antibodies, the limited utility of PCSK9 inhibitors in the central nervous system, and the cost-effectiveness of PCSK9 inhibitors.
Keywords: PCSK9; LDL receptor; monoclonal antibodies; anti-sense oligonucleotide; mimetic peptides; adnectin; CRISPR/Cas9 platform; berberine; oleanolic acid; neuronal apoptosis; coronary artery disease; cholesterol metabolism
Acta Pharmacologica Sinica (2017) 38: 301311; doi: 10.1038/aps.2016.134; published online 16 Jan 2017
Introduction
Cardiovascular diseases that occur in patients who have high levels of low-density lipoprotein cholesterol (LDL-C) are a leading cause of death in developed countries[1, 2]. Increased levels of LDL-C are considered a major risk factor for coronary artery disease (CHD) and for the development of atherosclerotic plaques in arteries[3, 4]. Cardiovascular risk is decreased by 22% when LDL-C is reduced by 24 mg/dL or 38.5 mg/dL[5, 6].
Loss-of-function mutations in the...