Targeted Degradation of PCSK9 In Vivo by Autophagy-Tethering Compounds

  • J Med Chem. 2024 Jan 11;67(1):433-449. doi: 10.1021/acs.jmedchem.3c01634.
Zhirong Ouyang  1 ,  Muye Ma  2 ,  Ziwen Zhang  1 ,  Hongyu Wu  1 ,  Yongxing Xue  1 ,  Yuting Jian  2 ,  Kai Yin  1 ,  Shaokun Yu  2 ,  Chunchang Zhao  3 ,  Wei Guo  2 ,  Xianfeng Gu  1
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. Key Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research Center, Institute of Fine Chemicals, School of Chemistry and Molecular Engineering, Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai 200237, China.
PMID: 38112492 DOI: 10.1021/acs.jmedchem.3c01634
Abstract

Proprotein convertase subtilisin/kexin type-9 (PCSK9), a secreted protein that is synthesized and spontaneously cleaved in the endoplasmic reticulum, has become a hot lipid-lowering target chased by pharmaceutical companies in recent years. Autophagosome-tethering compounds (ATTECs) represent a new strategy to degrade targeted biomolecules. Here, we designed and synthesized PCSK9·ATTECs that are capable of lowering PCSK9 levels via Autophagy in vivo, providing the first report of the degradation of a secreted protein by ATTECs. OY3, one of the PCSK9·ATTECs synthesized, shows greater potency to reduce plasma low-density lipoprotein Cholesterol (LDL-C) levels and improve atherosclerosis symptoms than treatment with the same dose of simvastatin. OY3 also significantly reduces the high expression of PCSK9 caused by simvastatin administration in atherosclerosis model mice and subsequently increases the level of low-density lipoprotein receptor, promoting simvastatin to clear plasma LDL-C and alleviate atherosclerosis symptoms. Thus, we developed a new candidate compound to treat atherosclerosis that could also promote statin therapy.

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