title: Inhibition of pro-protein convertase subtilisin kexin 9 [corrected] (PCSK-9) as a treatment for hyperlipidaemia.
abstract: BACKGROUND
  Pro-protein [corrected] convertase subtilisin kexin (PCSK)-9 is a newly discovered protein involved in intracellular and extracellular regulation of low-density lipoprotein receptor (LDLR) expression. Autosomal dominant activating mutations in PCSK-9 cause familial hypercholesterolaemia whereas inactivating mutations in man reduce LDL cholesterol (LDL-C) and are associated with a decreased lifetime risk of cardiovascular events.
  
  
  METHODS
  As PCSK-9 binds to the LDLR, a number of approaches involving small molecule or peptide inhibition of binding, antibody-mediated inactivation of binding and the use of antisense oligonucleotides are being investigated as therapeutic approaches to lower LDL-C in man. This article reviews the biochemistry and physiology of PCSK-9 and details the efforts made to design novel molecules with the ability to inhibit PCSK-9 activity. Work in animal models has confirmed that reducing PCSK-9 expression can reduce atherosclerosis in mice, rats and primates. Monoclonal antibodies such as REGN-727 and AMG-145 have been shown to reduce LDL-C in patients with familial hypercholesterolaemia already treated with statins or healthy normocholesterolaemic controls.
  
  
  CONCLUSIONS
  PCSK-9 inhibition is a potentially interesting novel addition to the armamentarium of LDL-C reducing drugs. Its effects in reducing LDL-C will need to be confirmed to reduce CVD events in large-scale clinical trials.
authors.affiliation: St. Thomas' Hospital Campus, Department of Chemical Pathology , Lambeth Palace Road, London, UK. Anthony.Wierzbicki@kcl.ac.uk
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Wierzbicki
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Hardman
authors.forename: Adie
authors.initials: A
authors.lastname: Viljoen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012697:Serine Endopeptidases / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000960:Hypolipidemic Agents; D011480:Protease Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C577155:evolocumab