title: PCSK9: an emerging target for treatment of hypercholesterolemia.
abstract: BACKGROUND
  Increased plasma low-density lipoprotein (LDL) cholesterol is a significant risk factor for cardiovascular disease. Plasma LDL-cholesterol is controlled through its uptake into cells upon binding the LDL receptor (LDLR). Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the LDLR and promotes its degradation, resulting in increased plasma LDL-cholesterol. Inhibiting the action of PCSK9 on the LDLR has emerged as a novel therapeutic target for hypercholesterolemia.
  
  
  METHODS
  We briefly describe the identification and initial characterisation of PCSK9, before detailing the molecular mechanisms involved in its interaction with the LDLR. We highlight the potential sites for therapeutic intervention in this pathway and describe the current status of therapeutic approaches, including blocking antibodies, siRNA, antisense oligonucleotides and small-molecule inhibitors. The potential limitations of such approaches are also discussed.
  
  
  CONCLUSIONS
  There is a wealth of evidence indicating that inhibition of PCSK9 is a highly desirable approach to combat hypercholesterolemia, with several agents in preclinical and clinical development. However, further research is required to fully understand the biological role of PCSK9 and whether its inhibition may have adverse effects in certain groups of patients, for example, those with liver disease.
authors.affiliation: University of Leeds, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, Leeds LS2 9JT, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Duff
authors.forename: Nigel M
authors.initials: NM
authors.lastname: Hooper
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology / Q000627:therapeutic use; D008078:Cholesterol, LDL / Q000097:blood / Q000378:metabolism*; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000235:genetics; D058990:Molecular Targeted Therapy; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011485:Protein Binding; D034622:RNA Interference; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology
chemical_list: D057134:Antibodies, Neutralizing; D008078:Cholesterol, LDL; D011973:Receptors, LDL; D015842:Serine Proteinase Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases