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

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.