GPCR antagonism via rewiring of receptor trafficking and degradation

Abstract

G protein–coupled receptors (GPCRs) represent one of the most important yet incompletely addressed classes of therapeutic targets1. Here, we report a novel strategy for functional GPCR antagonism via bispecific antibody-mediated endocytosis and lysosomal degradation. GPCR-TfR1 targeting chimeras (GTACs) achieve potent and selective downregulation of multiple GPCRs, including BILF1, RXFP1, and CCR6––viral, cancer, and immune targets that have been difficult to drug2-4. GTACs lead to complete inhibition of receptor signaling, including constitutive signaling, with >1–2 orders of magnitude greater potency than conventional antibody antagonists. Using protein engineering and multicolor live-cell imaging, we establish a context-dependent degrader design and elucidate the cellular mechanisms with broad relevance for degrader technology. The GTAC platform establishes induced endocytosis and rewiring protein trafficking as a new paradigm for therapeutic GPCR modulation.