title: PCSK9: Regulation and Target for Drug Development for Dyslipidemia.
abstract: Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a secreted zymogen expressed primarily in the liver. PCSK9 circulates in plasma, binds to cell surface low-density lipoprotein (LDL) receptors, is internalized, and then targets the receptors to lysosomal degradation. Studies of naturally occurring PCSK9 gene variants that caused extreme plasma LDL cholesterol (LDL-C) deviations and altered atherosclerosis risk unleashed a torrent of biological and pharmacological research. Rapid progress in understanding the physiological regulation of PCSK9 was soon translated into commercially available biological inhibitors of PCSK9 that reduced LDL-C levels and likely also cardiovascular outcomes. Here we review the swift evolution of PCSK9 from novel gene to drug target, to animal and human testing, and finally to outcome trials and clinical applications. In addition, we explore how the genetics-guided path to PCSK9 inhibitor development exemplifies a new paradigm in pharmacology. Finally, we consider some potential challenges as PCSK9 inhibition becomes established in the clinic.
authors: Department of Biochemistry, Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5B7; email: aburke42@uwo.ca , jdron@uwo.ca , hegele@robarts.ca , mhuff@uwo.ca.
authors: Amy C
authors: AC
authors: Burke
authors: Department of Biochemistry, Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5B7; email: aburke42@uwo.ca , jdron@uwo.ca , hegele@robarts.ca , mhuff@uwo.ca.
authors: Jacqueline S
authors: JS
authors: Dron
authors: Department of Biochemistry, Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5B7; email: aburke42@uwo.ca , jdron@uwo.ca , hegele@robarts.ca , mhuff@uwo.ca.|Department of Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5B7.
authors: Robert A
authors: RA
authors: Hegele
authors: Department of Biochemistry, Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5B7; email: aburke42@uwo.ca , jdron@uwo.ca , hegele@robarts.ca , mhuff@uwo.ca.|Department of Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5B7.
authors: Murray W
authors: MW
authors: Huff
mesh_terms: D000818:Animals; D008078:Cholesterol, LDL / Q000037:antagonists & inhibitors / Q000097:blood; D016503:Drug Delivery Systems / Q000379:methods* / Q000639:trends; D055808:Drug Discovery / Q000379:methods* / Q000639:trends; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy / Q000201:enzymology; D000091362:PCSK9 Inhibitors; D000071449:Proprotein Convertase 9 / Q000502:physiology*
chemical_list: D008078:Cholesterol, LDL; D004791:Enzyme Inhibitors; D000091362:PCSK9 Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: PCSK9 inhibitors; cardiovascular disease; low-density lipoprotein cholesterol; low-density lipoprotein receptor; proprotein convertase subtilisin/kexin type-9