Advances in Cyclic Peptides Targeting G Protein‐Coupled Receptors

Abstract

Peptide‐responsive G protein‐coupled receptors (GPCRs) often recognize endogenous peptide ligands through extended receptor interfaces, providing opportunities for peptide‐based ligands to engage receptor contacts that conventional small molecules struggle to access effectively. In this context, cyclic peptides are more than stabilized peptide analogs: their constrained topologies can preorganize key pharmacophoric elements, support engagement with extended orthosteric or allosteric receptor interfaces, and allow precise tuning of selectivity and signaling output. In this review, we discuss cyclic peptides targeting peptide‐responsive GPCRs through three connected dimensions: natural macrocyclic ligands and scaffolds, chemical strategies for topological and functional optimization, and emerging discovery platforms for GPCR‐active macrocycles. Specifically, we examine how endogenous cyclic peptides, venom‐derived peptides, plant cyclotides, and microbial macrocycles provide structurally defined templates for probing GPCR recognition, and how engineering approaches, including bridge replacement, conformational locking, residue modification, and half‐life extension, have expanded their utility as both bioactive ligands and molecular probes. We further highlight discovery technologies (e.g., mRNA display, phage display, cell‐based screening, and structure‐ and computation‐guided design) that are advancing the discovery and optimization of macrocycles with improved receptor specificity and pharmacological properties. Together, these advances position cyclic peptides as a topology‐guided molecular strategy for dissecting peptide–GPCR recognition and developing next‐generation therapeutics.