Table 3 The characteristics of different lysosome-based degraders
From: Targeted protein degradation: advances in drug discovery and clinical practice
Feature | AUTAC | LYTAC | ATTEC | CMA-based degrader |
|---|---|---|---|---|
Mechanism | Utilize autophagy pathways to degrade target proteins or organelles | Degrade cell surface proteins via lysosomal pathways | Guide proteins to autophagosomes for degradation | Direct lysosomal degradation via chaperone proteins |
Target types | Intracellular proteins and organelles | Cell surface proteins | Intracellular proteins | Intracellular proteins with KFERQ sequence |
Poven target | Metalloprotease, dysfunctional mitochondria | Extracellular protein, transmembrane glycoprotein, immune checkpoint, kinase | PolyQ expansion proteins, kinase, lipid droplets | Proteins, α-synuclein, kinase |
Advantage | Remove targeted cytosolic proteins or mitochondria in xenophagy | Degrade the extracellular secreted proteins and plasma membrane-associated proteins; can be liver-specific | Allele selective for a specific protein | Possible solution for the treatment of diseases caused by misfolded proteins |
Limitation | The mechanism of K63 polyubiquitination induced by S-guanylation is still unknown | Cannot be applied to intracellular targets | The binding site in LC3 is not yet known | The delivery and stability of degrader peptides need to be resolved |
