2. Academic Validation
  3. Tunable Biased Signaling of the Angiotensin II Type 1 Receptor for Inotropy via C-Terminal Peptide Engineering and Allosteric Site Targeting

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

  • J Med Chem. 2026 Feb 12;69(3):2063-2081. doi: 10.1021/acs.jmedchem.5c01259.
Margot Hadjadj 1 2 3,  Malihe Hassanzadeh 1 3,  Justin Martel 1 2 3,  Marie-Frédérique Roy 1 2 3,  Hugo Giguère 2 3,  Alexandre Murza 1 3,  Brian J Holleran 1 3,  Yoon Namkung 4,  Ulrike Froehlich 1 3,  Richard Leduc 1 3,  Mannix Auger-Messier 2 3,  Stéphane A Laporte 4 5,  Pierre-Luc Boudreault 1 3
Affiliations

Affiliations

  • 1 Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Centre de Recherche du CHUS, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.
  • 2 Département de Médecine─Service de Cardiologie, Faculté de Médecine et des Sciences de la Santé, Centre de Recherche du CHUS, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.
  • 3 Institut de Pharmacologie de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada.
  • 4 Department of Medicine, Research Institute of the McGill University Health Center (RI-MUHC), McGill University, Montréal, Québec H4A 3J1, Canada.
  • 5 Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3G 1Y6, Canada.
PMID: 41545027 DOI: 10.1021/acs.jmedchem.5c01259
Abstract

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.

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