Proprotein convertase subtilisin/kexin type 9 (PCSK9): From structure–function relation to therapeutic inhibition

• Published in: Nutrition, metabolism, and cardiovascular diseases Vol. 21; no. 11; pp. 835 - 843
• Main Authors: Tibolla, G, Norata, G.D, Artali, R, Meneghetti, F, Catapano, A.L
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2011
• Subjects: Animals; Cardiovascular; Cholesterol, LDL - blood; clinical trials; genes; Humans; hypercholesterolemia; Hypercholesterolemia - drug therapy; Hypercholesterolemia - genetics; hypocholesterolemia; Hypolipidemic Agents; LDL receptor; low density lipoprotein cholesterol; monoclonal antibodies; Mutation; oligonucleotides; PCSK9; Plasma LDL-cholesterol; Proprotein Convertase 9; Proprotein Convertases; Receptors, LDL - metabolism; Serine Endopeptidases - chemistry; Serine Endopeptidases - genetics; Serine Endopeptidases - physiology; Serine Proteinase Inhibitors - therapeutic use; small interfering RNA; Statins; Structure-Activity Relationship; subtilisin; FH; LDL-C; ADH; PCSK9; sterol responsive element binding protein; short interfering RNA; LDL-cholesterol; apolipoprotein B-100; LDL; VLDL; familial hypercholesterolemia; LDLR; Statins; apolipoprotein E receptor 2; autosomal dominant hypercholesterolemia; SREBP; apoER2; Proprotein convertase subtilisin/kexin type 9; HMG CoA; siRNA; apoB-100; 3-hydroxy-3-methylglutaryl coenzyme A; LDL receptor; low-density lipoprotein; mAb; very low-density lipoprotein; coronary heart disease; monoclonal antibody; CHD; Plasma LDL-cholesterol
• ISSN: 0939-4753; 1590-3729
• DOI: 10.1016/j.numecd.2011.06.002

Abstract Aims 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. Data synthesis 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. Conclusion 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.