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Updated: Apr 12, 2026
A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
PCSK9 (Proprotein convertase subtilisin/kexin type 9) inhibitors: past, present, and the future
Yuichi J Shimada1, Christopher P Cannon2
1Harvard Clinical Research Institute, Boston, MA, USA Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA yshimada@partners.org.
Insights
New Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors significantly lower LDL-C by 50-70%. These advanced therapies offer further cardiovascular event risk reduction beyond statins for specific patient groups.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Genetics
Background:
- Statins have reduced cardiovascular events by lowering LDL-C.
- Certain patient groups require additional LDL-C reduction beyond statin therapy.
Purpose of the Study:
- To review the development of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors.
- To highlight the progression from genetic discovery to clinical application.
Main Methods:
- Review of preclinical and clinical studies (Phases 1-3) on PCSK9 inhibitors.
- Analysis of genetic mutation discovery and its clinical impact.
- Examination of large clinical outcomes trials.
Main Results:
- PCSK9 inhibitors achieve 50-70% LDL-C reduction as monotherapy or with statins.
- Rapid drug development pathway from gene discovery to clinical trials.
Conclusions:
- PCSK9 inhibitors represent a significant advancement in cholesterol-lowering therapy.
- Further research and clinical application are ongoing, with challenges to address.
Abstract:
Reduction in low-density lipoprotein cholesterol (LDL-C), mainly with statins, has decreased the risk of cardiovascular events over the last few decades. However, there are several patient populations that warrant further decrease in LDL-C by additional cholesterol-lowering therapy other than statins. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a new class of drugs that have been shown to further decrease LDL-C by 50-70% when administered as a monotherapy or on a background therapy with statins. Proprotein convertase subtilisin/kexin type 9 inhibitors are also an excellent example of drug development in which discovery of gene mutations and its clinical effects have rapidly progressed into successful preclinical and clinical studies with multiple Phases 1-3 clinical trials completed or ongoing to date. This review summarizes the rapid evolution of the drug from genetic discovery to identification of targets for the drugs, to animal and human testing, and to large clinical outcomes trials, followed by discussion on foreseeable challenges of PCSK9 inhibitors.
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