Related Experiment Video
Updated: Jul 23, 2025
A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition: The Big Step Forward in Lipid Control
Rishi Rikhi1, Michael D Shapiro1
1Center for Prevention of Cardiovascular Disease, Section on Cardiovascular Medicine, Department of Internal Medicine, Wake Forest University School of Medicine Winston-Salem, NC, US.
Abstract:
The breakthrough discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) 20 years ago revolutionised the current understanding of cholesterol homeostasis. Genetic studies have shown that gain-of-function mutations in PCSK9 lead to elevated LDL cholesterol and increased risk of atherosclerotic cardiovascular disease, while loss-of-function mutations in PCSK9 result in lifelong low levels of circulating LDL cholesterol and dramatic reduction in atherosclerotic cardiovascular disease. Therapies inhibiting PCSK9 lead to a higher density of LDL receptor on the surface of hepatocytes, resulting in greater ability to clear circulating LDL. Thus far, randomised controlled trials have shown that subcutaneous fully human monoclonal antibodies targeting PCSK9, evolocumab and alirocumab, and PCSK9 silencing with inclisiran result in drastic reductions in LDL cholesterol. Additionally, several novel strategies to target PCSK9 are in development, including oral antibody, gene silencing, DNA base editing and vaccine therapies. This review highlights the efficacy, safety and clinical use of these various approaches in PCSK9 inhibition.
Insights
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition significantly lowers LDL cholesterol. This review covers current and emerging PCSK9 therapies for cardiovascular disease risk reduction.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) discovery revolutionized cholesterol homeostasis understanding.
- PCSK9 mutations influence LDL cholesterol levels and cardiovascular disease risk.
- PCSK9 inhibition enhances LDL receptor density on hepatocytes, increasing LDL clearance.
Purpose of the Study:
- To review the efficacy, safety, and clinical use of various PCSK9 inhibition strategies.
- To highlight current PCSK9 targeting therapies and novel approaches under development.
Main Methods:
- Review of randomized controlled trials for PCSK9 inhibitors.
- Analysis of genetic studies on PCSK9 function and dysfunction.
- Assessment of emerging PCSK9 targeting strategies including gene silencing, base editing, and vaccines.
Main Results:
- Subcutaneous monoclonal antibodies (evolocumab, alirocumab) and inclisiran demonstrate significant LDL cholesterol reduction.
- Genetic studies confirm the link between PCSK9 function and cardiovascular risk.
- Novel PCSK9 therapies show promise for future cardiovascular disease management.
Conclusions:
- PCSK9 inhibition is a validated strategy for lowering LDL cholesterol and reducing atherosclerotic cardiovascular disease risk.
- A diverse range of PCSK9 targeting therapies are available and in development, offering various clinical applications.
Related Concept Videos
01:20Lipid-Lowering Drugs: Statins and Miscellaneous Agents
01:06Lipid Digestion
01:24Glucagon-like Receptor Agonists
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by...
01:23Dipeptidyl Peptidase 4 Inhibitors
01:24Lipid Absorption
These breakdown products bind with bile salts and lecithin to form micelles, which quickly pass between microvilli to come in close contact with the apical...
01:25Lipid Catabolism