Targeted Degradation of PCSK9 In Vivo by Autophagy-Tethering Compounds

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 lipidlowering 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.

Exploring Arylidene-Indolinone Ligands of Autophagy Proteins LC3B and GABARAP

“…17 Similarly, Zhao, Guo, Gu, and coworkers found that changes in the linker structure within their PCSK9 ATTEC compounds resulted in an increase in binding to LC3B from 9.88 μM to 5.69 μM. 22 Given our results, it is possible that positive contributions to binding by the linker attached to the C11 hydroxyl or oxindole amide compensates for the decrease in binding to LC3/GABARAP proteins caused by substitution at these positions.…”

“…17 More recently, Gu and coworkers reported an ATTEC that incorporated 1 to degrade the protein PCSK9 as a potential atherosclerosis therapy. 22 Similarly, Dong and coworkers recently described an ATTEC using 1 to degrade PDEδ, an emerging target for pancreatic cancer therapy. 29…”

“…17 More recently, Gu and coworkers reported an ATTEC that incorporated 1 to degrade the protein PCSK9 as a potential atherosclerosis therapy. 22 Similarly, Dong and coworkers recently described an ATTEC using 1 to degrade PDEδ, an emerging target for pancreatic cancer therapy. 29 These findings suggested that 1 could be used in selective and modular fashion to bind LC3/GABARAP proteins and induce the degradation of other proteins and cellular components via autophagy.…”

“…These compounds tether proteins or cellular components of interest to the autophagosome, leading to the degradation of the liganded protein, organelle, or cellular component. [17][18][19][20][21][22][23][24][25][26][27][28][29] GW5074 (Fig. 1, hereafter called compound 1) was one of the earliest small molecules reported to bind LC3B, the most wellstudied LC3/GABARAP protein.…”

Discovery of LLC355 as an Autophagy-Tethering Compound for the Degradation of Discoidin Domain Receptor 1

“…Autophagosome-tethering compounds (ATTECs) have emerged as a new technology in targeted protein degradation. − As a heterobifunctional molecule, ATTECs recruit the protein of interest (POI) to autophagy key protein LC3 in the phagophore membrane and subsequently induce POI degradation through the autophagy lysosomal pathway. ATTECs can thus disrupt the enzymatic and nonenzymatic functions of the kinase by depleting its scaffold.…”