Tunable Biased Signaling of the Angiotensin II Type 1 Receptor for Inotropy via C‑Terminal Peptide Engineering 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
activating G protein or β-arrestin pathways offer therapeutic
promise, but the molecular determinants of this signaling bias and
its physiological implications remain poorly understood. This study
profiles AngII analogs with C-terminal Phe8 modifications,
identifies compounds 11, 12, and 29a as exhibiting differential Gαq activation while
retaining potent β-arrestin recruitment. Notably, 12 with low levels of Gαq activity, enhances left
ventricular ejection fraction with limited pressor responses in normotensive
rats. In contrast, other analogs with variably superior Gαq activity do not promote inotropy. Molecular modeling suggests
that the flexible side chain of 12 accesses a deep allosteric
pocket within AT1R, driving its unique signaling profile. 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.