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Updated: Jun 20, 2026

A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
08:14

A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9

Published on: August 28, 2018

Targeting PCSK9 for the treatment of hypercholesterolemia

Joseph A Hedrick1

  • 1Schering-Plough Research Institute, Department of Cardiovascular and Metabolic Disease Research, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. joseph.hedrick@spcorp.com

Current Opinion in Investigational Drugs (London, England : 2000)
|August 26, 2009
PubMed

Insights

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor levels and cholesterol. Inhibiting PCSK9 offers a therapeutic strategy for managing high LDL-cholesterol, with RNAi showing promise.

Area of Science:

  • Biochemistry
  • Genetics
  • Cardiovascular Research

Background:

  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of LDL receptor (LDLR) degradation.
  • PCSK9 activity directly influences serum LDL-cholesterol (LDL-C) levels.
  • Genetic variations in PCSK9 correlate with altered LDL-C levels and cardiovascular risk.

Purpose of the Study:

  • To investigate PCSK9 as a therapeutic target for modulating serum LDL-C.
  • To explore the feasibility of biologically inhibiting PCSK9.
  • To assess the progress of therapeutic strategies targeting PCSK9.

Main Methods:

  • Analysis of gain-of-function and loss-of-function PCSK9 mutations in humans.
  • Examination of PCSK9 expression effects in mouse models.
  • Review of preclinical RNAi-based therapeutic programs targeting PCSK9.

Main Results:

  • Gain-of-function PCSK9 mutations lead to high LDL-C; loss-of-function mutations confer protection against heart disease.
  • PCSK9 deficiency in mice increases LDLR and reduces cholesterol; overexpression has the opposite effect.
  • RNAi-based PCSK9 inhibition is in advanced preclinical development.

Conclusions:

  • PCSK9 is a validated target for controlling LDL-C.
  • Biological inhibition of PCSK9 is a feasible therapeutic approach.
  • While RNAi strategies are advancing, small-molecule inhibitors for PCSK9 face development challenges.

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