Tunable Bias Signaling of the Angiotensin II Type 1 Receptor for Inotropy via C-Terminal Peptide Modifications and Allosteric Site Targeting

The angiotensin II (AngII) type 1 receptor (AT1R) is a key prototypical G protein-coupled receptor in cardiovascular regulation. Biased agonists that activate G protein or β-arrestin pathways provide promising therapeutic potential, but the molecular determinants for this signaling bias and its physiological implications remain poorly understood. This study profiles AngII analogs with modifications at the C-terminal Phe⁸, revealing that analogs 11, 12, and 29a exhibit varying degrees of Gα_q engagement while maintaining potent β-arrestin recruitment. Notably, 12 enhances left ventricular ejection fraction with minimal pressor responses in normotensive rats, while other analogs with variable Gα_q activity do not promote inotropy. Molecular modeling indicates that the unique profile of 12 results from its flexible long side chain engaging a deep allosteric pocket within AT1R. This study demonstrates that engineering AngII’s C-terminus enables selective tuning of AT1R signaling to control arterial versus cardiac responses, providing strategies for developing improved cardiovascular therapeutics.