title: Lowering serum lipids via PCSK9-targeting drugs: current advances and future perspectives.
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 first describes the 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 field, 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.
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China.
authors.forename: Ni-Ya
authors.initials: NY
authors.lastname: He
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Ren
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China.
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Pan
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China.
authors.forename: Mei-Mei
authors.initials: MM
authors.lastname: Wang
authors.affiliation: Medical College, Hunan University of Chinese Medicine, Changsha 410208, China.
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Wen
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China.
authors.forename: Zhi-Sheng
authors.initials: ZS
authors.lastname: Jiang
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China.
authors.forename: Zhi-Han
authors.initials: ZH
authors.lastname: Tang
authors.affiliation: Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang 421001, China.
authors.forename: Lu-Shan
authors.initials: LS
authors.lastname: Liu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000924:Anticholesteremic Agents / Q000494:pharmacology; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D004720:Endonucleases / Q000235:genetics; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D058990:Molecular Targeted Therapy; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D000091362:PCSK9 Inhibitors; D011110:Polymorphism, Genetic; D000071449:Proprotein Convertase 9 / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000924:Anticholesteremic Agents; D000960:Hypolipidemic Agents; D016376:Oligonucleotides, Antisense; D000091362:PCSK9 Inhibitors; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D015842:Serine Proteinase Inhibitors; C000598888:bococizumab; D004720:Endonucleases; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9