Hepatocyte-Targeted Cyclic Peptide LYTACs for PCSK9 Degradation and LDL Cholesterol Metabolic Regulation - PubMed
6 hours ago
- #PCSK9 degradation
- #cholesterol regulation
- #LYTACs
- The study introduces cyclic peptide-based lysosome-targeting chimeras (LYTACs), LY1 and LY2, designed to degrade PCSK9 and regulate LDL cholesterol.
- LY1 and LY2 are created by conjugating high-affinity cyclic peptides (CP1/CP2) with triantennary N-acetylgalactosamine (tri-GalNAc) for hepatocyte-specific targeting via ASGPR.
- In Huh7 cells, LY1/LY2 effectively reduced extracellular PCSK9 levels and restored LDL uptake, outperforming non-degradative cyclic peptides.
- Mechanistic studies confirmed that the degradation process involves ASGPR-dependent endocytosis and lysosomal degradation.
- In hyperlipidemic mice, LY1 treatment significantly depleted circulating PCSK9 and improved lipid profiles, demonstrating therapeutic potential for sustained cholesterol regulation.