Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins - PubMed
7 hours ago
- #extracellular-proteins
- #sortilin-progranulin-interaction
- #targeted-protein-degradation
- Introduction of SORTACs (SORtilin-based lysosome TArgeting Chimeras) for targeted degradation of extracellular proteins via the lysosome, extending beyond traditional PROTACs that degrade cytosolic proteins in the proteasome.
- SORTACs function by reshaping the sortilin-progranulin interaction to induce ternary complex formation, endocytosis, and subsequent degradation, with activity that can be genetically encoded or chemically conjugated.
- Demonstrated applications include converting IgG-binding nanobodies to IgG-degrading ones, modifying therapeutic antibodies to drive target degradation, and developing small molecule SORTACs with nanomolar potency against inflammatory proteins like TNFα and vanin-1.
- SORTACs offer a modular platform for rapid degrader development against extracellular targets, highlighting potential wide impact in drug discovery, with patent applications and financial interests disclosed by some authors.