Targeting the Intracellular GPCR Core: A New Paradigm for Rationally Designing Biased Neuropeptide Ligands
- Identifying a conserved intracellular allosteric pocket on GPCRs, to design small molecules that directly modulate G-protein engagement, enabling unusually strong and clean pathway-selective signaling bias
- Selectively restricting or promoting access of specific transducers at the GPCR core, to allow rational tuning of signaling outputs, achieving desired therapeutic pathways while minimizing on-target side effects
- Leveraging a pocket that is conserved yet structurally variable across the GPCR superfamily, to provide a scalable framework for tailoring receptor-specific biased ligands and discovering new activities guided by ternary-complex insight