The ring size of monocyclic ET‐1 controls selectivity and signaling efficiency at both endothelin receptor subtypes

Cardiovascular diseases (CVDs) like hypertension are a major cause for death worldwide. In the cardiovascular tissue, endothelin system—consisting of receptor subtypes A (ETAR) and B (ETBR) mixed agonist 1 (ET-1)—is key player in regulation vascular tone blood pressure. Tight control this system is required to maintain homeostasis; otherwise, can severe CVDs pulmonary artery hypertension. The high sequence homology between both limits development novel selective ligands. Identification small differences receptor–ligand interactions determination selectivity constraints crucial fine-tune ligand properties subsequent signaling events. Here, we report on ET-1 analogs their detailed pharmacological characterization. We generated simplified ET-1-derived monocyclic peptides provide an accessible synthesis route. By vitro characterization, demonstrated that G protein arrestin recruitment activated ETBR remain intact, whereas activation ETAR depends intramolecular ring size. Increasing structure reduces activity at shifts peptide toward selectivity. All displayed efficient ETBR-mediated by 3 recruitment. Our study provides in-depth characterization ET-1/ETAR ET-1/ETBR interactions, which has potential future endothelin-based drugs CVD treatment. identification Lys9 labeling, peptide-mediated shuttling proposed.