A fatty-acid-modified peptide degrader clears TGF-βR1 through the lysosome
- Instead of merely occupying TGF-βR1, the authors aim to remove it, re-engineering a caveolin-derived antifibrotic peptide with structure-guided optimization.
- Adding a built-in lysosome-targeting module gave P2, which lowered receptor levels in a time- and dose-dependent, lysosome-dependent manner.
- Fatty-acid conjugation produced P2-FA with better stability and pharmacokinetics.
- P2-FA dampened profibrotic signaling in activated hepatic stellate cells and eased collagen deposition and liver injury in a mouse fibrosis model.
💡 Points Based on the abstract
Peptide-driven lysosomal clearance needs controls that separate true degradation from receptor internalization or sequestration, such as a scrambled peptide and a version lacking the lysosome module, plus selectivity over other TGF-β family receptors. Fatty-acid conjugation is the classic half-life fix, though albumin binding can cut free exposure.
📄 Paper · Journal of Medicinal Chemistry ↗ A Modular Peptide Strategy for Targeted Lysosomal Degradation of TGF-βR1