Angiotensin II cyclic analogs as tools to investigate AT1R biased signaling mechanisms

TL;DR

This study investigates how cyclic analogs of angiotensin II influence biased signaling at the AT1 receptor, revealing that ligand conformation constraints can modulate receptor pathway activation and aid drug design.

Contribution

The paper introduces cyclic analogs of angiotensin II and demonstrates their ability to selectively bias AT1 receptor signaling pathways, advancing understanding of ligand-receptor conformational dynamics.

Findings

[Sar1Hcy3,5]AngII exhibits broad pathway activation except Gq.

Molecular dynamics show increased energy barrier for Gq activation with cyclic analogs.

Cyclic constraints on ligands can enhance biased agonism at GPCRs.

Abstract

G protein coupled receptors (GPCRs) produce pleiotropic effects by their capacity to engage numerous signaling pathways once activated. Functional selectivity (also called biased signaling), where specific compounds can bring GPCRs to adopt conformations that enable selective receptor coupling to distinct signaling pathways, continues to be significantly investigated. However, an important but often overlooked aspect of functional selectivity is the capability of ligands such as angiotensin II (AngII) to adopt specific conformations that may preferentially bind to selective GPCRs structures. Understanding both receptor and ligand conformation is of the utmost importance for the design of new drugs targeting GPCRs. In this study, we examined the properties of AngII cyclic analogs to impart biased agonism on the angiotensin type 1 receptor (AT1R). Positions 3 and 5 of AngII were substituted for cysteine and homocysteine residues ([Sar1Hcy3,5]AngII, [Sar1Cys3Hcy5]AngII and [Sar1Cys3,5]AngII) and the resulting analogs were evaluated for their capacity to activate the Gq/11, G12, Gi2, Gi3, Gz, ERK and \b{eta}-arrestin (\b{eta}arr) signaling pathways via AT1R. Interestingly, [Sar1Hcy3,5]AngII exhibited potency and full efficacy on all pathways tested with the exception of the Gq pathway. Molecular dynamic simulations showed that the energy barrier associated with the insertion of residue Phe8 of AngII within the hydrophobic core of AT1R, associated with Gq/11 activation, is increased with [Sar1Hcy3,5]AngII. These results suggest that constraining the movements of molecular determinants within a given ligand by introducing cyclic structures may lead to the generation of novel ligands providing more efficient biased agonism.