State-specific Peptide Design Targeting G Protein-coupled Receptors

G protein-coupled receptors (GPCRs) play critical roles in various physiological processes and serve as pivotal targets for drug discovery. Peptides are particularly compelling therapeutic agents for targeting GPCRs, as they frequently exhibit superior affinity, selectivity, and potency compared to small-molecule drugs. However, the states (active and inactive) of GPCRs profoundly influence their interactions with ligands, highlighting the need for state-specific strategies in peptide design. To address this, we developed an efficient state-specific peptide design pipeline targeting GPCRs. This framework enables the tailored design of agonists or antagonists based on the active or inactive conformational states of GPCR structures. A state-specific folding model, optimized for GPCR-peptide complexes, was used to select high-potential peptides from the pool of designed candidates. Using this approach, we successfully identified both agonist and antagonist peptides for the Apelin Receptor (APJR) and the Growth Hormone Secretagogue Receptor (GHSR), as well as a competitive inhibitor for the Glucagon-Like Peptide-1 Receptor (GLP-1R).