PCSK9 Targeted Autophagosome-Tethering Compounds: Design, Synthesis, and Antiatherosclerosis Evaluation

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.