The biology of PCSK9 from the endoplasmic reticulum to lysosomes: new and emerging therapeutics to control low-density lipoprotein cholesterol

Drug Des Devel Ther. 2013 Oct 4;7:1135-48. doi: 10.2147/DDDT.S36984. eCollection 2013.

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) directly binds to the epidermal growth factor-like repeat A domain of low-density lipoprotein receptor and induces its degradation, thereby controlling circulating low-density lipoprotein cholesterol (LDL-C) concentration. Heterozygous loss-of-function mutations in PCSK9 can decrease the incidence of coronary heart disease by up to 88%, owing to lifelong reduction of LDL-C. Moreover, two subjects with PCSK9 loss-of-function mutations on both alleles, resulting in a total absence of functional PCSK9, were found to have extremely low circulating LDL-C levels without other apparent abnormalities. Accordingly, PCSK9 could represent a safe and effective pharmacological target to increase clearance of LDL-C and to reduce the risk of coronary heart disease. Recent clinical trials using anti-PCSK9 monoclonal antibodies that block the PCSK9:low-density lipoprotein receptor interaction were shown to considerably reduce LDL-C levels by up to 65% when given alone and by up to 72% in patients already receiving statin therapy. In this review, we will discuss how major scientific breakthroughs in PCSK9 cell biology have led to the development of new and forthcoming LDL-C-lowering pharmacological agents.

Keywords: LDL-cholesterol; LDLR; PCSK9; coronary heart disease; inhibitors; lipoproteins; monoclonal antibody therapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Anticholesteremic Agents / pharmacology*
  • Cholesterol, LDL / blood*
  • Coronary Disease / physiopathology
  • Coronary Disease / prevention & control
  • Drug Design
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Lysosomes / metabolism
  • Molecular Targeted Therapy
  • Mutation
  • Proprotein Convertase 9
  • Proprotein Convertases / antagonists & inhibitors
  • Proprotein Convertases / genetics
  • Proprotein Convertases / metabolism*
  • Receptors, LDL / metabolism
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*

Substances

  • Antibodies, Monoclonal
  • Anticholesteremic Agents
  • Cholesterol, LDL
  • Receptors, LDL
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases