GPCR antagonism via rewiring of receptor trafficking and degradation.

Bispecific antibody chimeras (GTACs) induce receptor degradation, achieving over 100-fold greater potency than traditional antagonists for multiple GPCRs.

• Why it matters: GPCRs are critical therapeutic targets but remain challenging to inhibit effectively, especially for receptors involved in viral, cancer, and immune processes. Overcoming this difficulty could unlock new treatment options.
• What they did: The study developed GTACs that target GPCRs and TfR1, promoting receptor endocytosis and lysosomal degradation, with detailed protein engineering and live-cell imaging to understand the cellular mechanisms involved.
• The result: This approach enables complete receptor signaling inhibition, including constitutive activity, and offers a versatile platform for therapeutic GPCR modulation through receptor trafficking rewiring.