From Structure to Function: Development of Relaxin‐3 Analogs and their Role in RXFP3 Signaling

Relaxin-3 is a two-chain neuropeptide of the insulin/relaxin superfamily and the cognate ligand for the G protein-coupled receptor RXFP3. Since its discovery, the relaxin-3/RXFP3 signaling system has emerged as a key regulator of feeding behavior, stress responses, arousal, addiction, and cognitive function. Recent structural studies, including the first cryo-electron microscopy structures of RXFP3 bound to relaxin-3 and small molecules, have provided significant insights into ligand-receptor interactions. Together with mutagenesis and pharmacological studies, these advances have facilitated the design of diverse RXFP3 ligands, ranging from simplified and/or stapled single-chain analogs of relaxin-3 to grafted scaffolds and small-molecule modulators. Such tools have been instrumental for probing relaxin-3 biology in vivo and highlight the system's therapeutic potential for treating anxiety, depression, obesity, binge eating, and alcohol use disorder. However, challenges remain, particularly regarding blood-brain barrier penetration, receptor subtype selectivity, pharmacokinetic optimization, and safe long-term modulation. This review summarizes current knowledge of relaxin-3 structure, receptor interactions, and pharmacology and highlights how advances in peptide chemistry, structural biology, and small-molecule design are enabling the rational development of RXFP3-targeted therapeutics.