title: Proprotein convertase subtilisin/kexin type 9 (PCSK9): from structure-function relation to therapeutic inhibition.
abstract: OBJECTIVE
  This short review aims at summarizing the current information on Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) structure and function focusing also on the therapeutic possibilities based on the inhibition of this protein.
  
  
  RESULTS
  PCSK9 has been recently discovered as the third gene involved in autosomal dominant hypercholesterolemia. PCSK9 binds and favors degradation of the low-density lipoprotein receptor (LDLR) and thereby modulates the plasma levels of LDL-cholesterol (LDL-C). Some of the natural occurring PCSK9 mutations increase the protein function (gain of function) and cause hypercholesterolemia, whereas loss of function mutations associate with hypocholesterolemia. Since the loss of a functional PCSK9 in humans is not associated with apparent deleterious effects, this protease is an attractive target for the development of lowering plasma LDL-C agents, either alone or in combination with statins.
  
  
  CONCLUSIONS
  Inhibition of PCSK9 is emerging as a novel strategy for the treatment of hypercholesterolemia and data obtained from pre-clinical studies show that use of monoclonal antibodies, antisense oligonucleotides and short interfering RNA are effective in reducing LDL-C, clinical studies, accompanied by a better understanding of PCSK9 biology, are now necessary to address whether these new compounds will have a future in clinical practice.
authors.affiliation: Department of Pharmacological Sciences, Università degli Studi di Milano, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Tibolla
authors.forename: G D
authors.initials: GD
authors.lastname: Norata
authors.forename: R
authors.initials: R
authors.lastname: Artali
authors.forename: F
authors.initials: F
authors.lastname: Meneghetti
authors.forename: A L
authors.initials: AL
authors.lastname: Catapano
mesh_terms: D000818:Animals; D008078:Cholesterol, LDL / Q000097:blood; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000235:genetics; D000960:Hypolipidemic Agents; D009154:Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011973:Receptors, LDL / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D008078:Cholesterol, LDL; D000960:Hypolipidemic Agents; D011973:Receptors, LDL; D015842:Serine Proteinase Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases