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 with 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).