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

Abstract

Targeted protein degradation (TPD) using PROteolysis TArgeting Chimeras (PROTACs) is a rapidly emerging therapeutic strategy for difficult-to-drug cytosolic proteins. PROTACs are heterobifunctional small molecules that bridge the target with an E3 ubiquitin ligase, destining it for degradation by the proteasome. They have the potential to be orally available and to act catalytically, switching the pharmacology from occupancy-driven to event-driven (1-3). Here we present a strategy for targeted degradation of extracellular proteins by reshaping the interaction between the broadly expressed lysosome sorting receptor sortilin and its ligand progranulin for engineering SORtilin-based lysosome TArgeting Chimeras (SORTACs). SORTACs induce ternary complex formation with the target and sortilin, followed by endocytosis and lysosomal degradation. SORTAC activity can be genetically encoded as demonstrated by converting an IgG binding nanobody to an IgG degrading nanobody or by chemical conjugation, enabling single step conversion of therapeutic antibodies from binding their target to driving its degradation. Importantly, using structure-based design, we generated small molecule SORTACs against the inflammatory cytokine TNFa with nanomolar range potency and with physicochemical properties like PROTACs. Our results demonstrate that SORTACs constitute a versatile and highly modular platform for rapid generation of degraders of in theory any extracellular target and with the potential to have wide impact in drug discovery.