Reshaping the progranulin/sortilin interaction for targeted degradation of extracellular proteins

Targeted protein degradation (TPD) using PROteolysis TArgeting Chimeras (PROTACs) is a powerful therapeutic strategy for degrading difficult-to-drug cytosolic proteins in the proteasome. Here, we present a strategy for extracellular TPD by reshaping the interaction between the lysosome sorting receptor sortilin and its ligand progranulin for engineering SORtilin-based lysosome TArgeting Chimeras (SORTACs). SORTACs induce ternary complex formation followed by endocytosis and target degradation. SORTAC activity can be genetically encoded, demonstrated by converting an IgG-binding nanobody to an IgG-degrading nanobody or by chemical conjugation, enabling conversion of therapeutic antibodies from binding their target to driving its degradation. Importantly, we generated PROTAC-like small molecule SORTACs with nanomolar range potency against two inflammatory proteins, the cytokine TNFa and the membrane protein vanin-1. Our results demonstrate that SORTACs constitute a modular platform for rapid generation of degraders of extracellular targets and with the potential to have wide impact in drug discovery.