2. Academic Validation
  3. PCSK9 Targeted Autophagosome-Tethering Compounds: Design, Synthesis, and Antiatherosclerosis Evaluation

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

  • J Med Chem. 2025 Apr 24;68(8):8190-8207. doi: 10.1021/acs.jmedchem.4c02915.
Hongyu Wu 1,  Ziwen Zhang 1,  Yongxing Xue 1,  Jiannan Guo 2,  Zhirong Ouyang 1,  Zhonglian Cao 3,  Wei Guo 2,  Qingwen Zhang 4,  Mo Wang 5,  Xianfeng Gu 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201301, China.
  • 2 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201301, China.
  • 3 Department of Biopharmaceuticals, School of Pharmacy, Fudan University, Shanghai 201301, China.
  • 4 State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai 201301, China.
  • 5 Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
PMID: 40226893 DOI: 10.1021/acs.jmedchem.4c02915
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.

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