β-Arrestins and disease-linked variants: opportunities for targeted modulation

G protein-coupled receptors orchestrate numerous physiological processes and represent the largest class of drug targets, yet their intracellular regulators, the β-arrestins, remain largely underexplored. Despite their crucial roles in receptor desensitization, trafficking, and signaling, few modulators have been identified, with limited isoform selectivity. Therapeutic efforts have mainly focused on receptor-level biased ligands to indirectly influence arrestin pathways. However, advances in small-molecule discovery and peptide design are now expanding the feasibility of directly modulating β-arrestins using structurally tailored ligands, primarily as research tools and potential therapeutic leads. Along with the recent identification of disease-associated mutations and first-generation modulators, these developments create new opportunities for selective and mutation-specific targeting. In this review, we summarize β-arrestin biology and signaling, highlight recent discoveries of disease-associated mutations and β-arrestin modulators, and discuss emerging strategies for precision drug development of arrestin-targeting compounds, with a focus on peptides.