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Updated: Jun 14, 2025
A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
Published on: August 28, 2018
PCSK9 Targeted Autophagosome-Tethering Compounds: Design, Synthesis, and Antiatherosclerosis Evaluation
Hongyu Wu1, Ziwen Zhang1, Yongxing Xue1
1Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201301, China.
Abstract:
Atherosclerosis is a multifaceted disease involving various cell types and complex mechanisms, and it is the main cause of cardiovascular disease. Proprotein convertase subtilisin/kexin type-9 (PCSK9) has been identified as an effective target for treating atherosclerosis; however, most current research focuses on biological drugs. Our work optimized the previously reported autophagosome-tethering compound OY3, and specifically, compound W6 induced PCSK9 degradation with a 5-fold increase in activity and a 6-fold increase in bioavailability. Compared to the currently marketed PCSK9 drug, siRNA, W6 demonstrated comparable antiatherosclerosis effects both in vivo and in vitro. W6 exhibited beneficial effects on hepatocytes, endothelial cells, macrophages, and vascular smooth muscle cells involved in the atherosclerosis process, making it a promising potential antiatherosclerosis drug. This work highlights the feasibility of ATTECs in degrading both intracellular and extracellular proteins, and our novel PCSK9-ATTEC W6 provides a valuable reference for the treatment of atherosclerotic diseases.
Insights
A novel compound, W6, effectively degrades PCSK9, showing promise for treating atherosclerosis. This autophagosome-tethering compound (ATTEC) offers a new therapeutic avenue for cardiovascular disease.
Area of Science:
- Biochemistry
- Pharmacology
- Cardiovascular Research
Background:
- Atherosclerosis is a complex cardiovascular disease driven by multiple cell types and mechanisms.
- Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a key therapeutic target for atherosclerosis.
- Current treatments primarily utilize biological drugs, necessitating exploration of novel therapeutic strategies.
Purpose of the Study:
- To optimize an autophagosome-tethering compound (ATTEC) for enhanced PCSK9 degradation.
- To evaluate the efficacy of the optimized compound (W6) in treating atherosclerosis.
- To assess the potential of W6 as an anti-atherosclerosis drug.
Main Methods:
- Optimization of a previously reported ATTEC (OY3) to develop compound W6.
- In vitro and in vivo assessment of W6's anti-atherosclerosis effects.
- Evaluation of W6's impact on hepatocytes, endothelial cells, macrophages, and vascular smooth muscle cells.
Main Results:
- Compound W6 demonstrated a 5-fold increase in PCSK9 degradation activity and a 6-fold increase in bioavailability compared to OY3.
- W6 exhibited comparable anti-atherosclerosis effects to siRNA, a marketed PCSK9 inhibitor.
- W6 showed beneficial effects across various cell types crucial to atherosclerosis pathology.
Conclusions:
- The novel PCSK9-targeting ATTEC, W6, is a potent inducer of PCSK9 degradation.
- W6 presents a promising therapeutic candidate for atherosclerosis treatment.
- This study validates the potential of ATTECs for degrading intracellular and extracellular proteins in disease treatment.
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