Related Experiment Video
Updated: Jan 7, 2026
08:14
A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
8.6K
CADD-engineered peptide protacs efficiently target PCSK9 for hypercholesterolemia in vivo
Gang Fan1, Weiming Guo2, Jingfen Lu3
1Medical Research Center, Affiliated Nanshan Hospital of Shenzhen University, Shenzhen, 518000, China; Pan-Vascular Research Group, Shenzhen University Affiliated Sixth Hospital, 518000, Shenzhen, Guangdong, China.
Metabolism: Clinical and Experimental
|December 25, 2025
Summary
A novel peptide degrader, Cadd4, effectively targets intracellular PCSK9, lowering LDL cholesterol. This computer-aided drug design approach offers a promising new strategy for managing hypercholesterolemia and cardiovascular disease.
Area of Science:
- Cardiovascular Research
- Drug Discovery
- Molecular Biology
Background:
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) elevates LDL cholesterol by degrading LDL receptors.
- Existing therapies for hypercholesterolemia have limitations, including cost, safety, and inability to target intracellular PCSK9.
Purpose of the Study:
- To develop a novel peptide-based degrader, Cadd4, targeting intracellular PCSK9 using computer-aided drug design (CADD).
- To evaluate the efficacy and safety of Cadd4 in preclinical models and human liver tissues.
Main Methods:
- Computer-aided drug design (CADD) and molecular docking to identify high-affinity peptide sequences.
- In vitro studies using LX-2 cells and in vivo experiments in high-fat diet-induced hypercholesterolemic mice.
- Biodistribution, toxicity assessments, and human liver tissue experiments to evaluate efficacy and safety.
Main Results:
- Cadd4 demonstrated efficient intracellular uptake and significant reduction of PCSK9 levels, upregulating LDLR expression.
- In mice, Cadd4 decreased hepatic PCSK9 by 38%, total cholesterol by 25%, and LDL-C by 29%.
- Cadd4 showed liver-specific accumulation, no systemic toxicity, and superior lipid-lowering efficacy compared to AZD0780 in human tissues.
Conclusions:
- Cadd4 is a promising CADD-designed therapeutic strategy for cholesterol management via intracellular PCSK9 degradation.
- This approach overcomes limitations of current PCSK9 therapies.
- Targeted protein degradation holds potential for treating cardiovascular diseases.
