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 <b>OY3</b>, and specifically, compound <b>W6</b> 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, <b>W6</b> demonstrated comparable antiatherosclerosis effects both <i>in vivo</i> and <i>in vitro</i>. <b>W6</b> 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 <b>W6</b> provides a valuable reference for the treatment of atherosclerotic diseases.