Evolution of Angiotensin Peptides and Peptidomimetics as Angiotensin II Receptor Type 2 (AT2) Receptor Agonists

Abstract

Angiotensin II receptor type 1 and 2 (AT1R and AT2R) are two G-protein coupled receptors that mediate most biological functions of the octapeptide Angiotensin II (Ang II). AT2R is upregulated upon tissue damage and its activation by selective AT2R agonists has become a promising approach in the search for new classes of pharmaceutical agents. We herein analyzed the chemical evolution of AT2R agonists starting from octapeptides, through shorter peptides and peptidomimetics to the first drug-like AT2R-selective agonist, C21, which is in Phase II clinical trials and aimed for idiopathic pulmonary fibrosis. Based on the recent crystal structures of AT1R and AT2R in complex with sarile, we identified a common binding model for a series of 11 selected AT2R agonists, consisting of peptides and peptidomimetics of different length, affinity towards AT2R and selectivity versus AT1R. Subsequent molecular dynamics simulations and free energy perturbation (FEP) calculations of binding affinities allowed the identification of the bioactive conformation and common pharmacophoric points, responsible for the key interactions with the receptor, which are maintained by the drug-like agonists. The results of this study should be helpful and facilitate the search for improved and even more potent AT2R-selective drug-like agonists.

Fuyuan Xingnao Decoction Promotes Angiogenesis Through the Rab1/AT1R Pathway in Diabetes Mellitus Complicated With Cerebral Infarction

“…AT1R is synthesized on the endoplasmic reticulum and transported to Golgi apparatus for post-translational modification, then to Ang II on the cell membrane surface to stimulate signaling pathways. Finally, it binds to Ang II AT1R to degrade lysosomes ( Vasile et al, 2020 ). In this process, vesicles transport neurotransmitters, proteins or other substances to specific cell sites ( Sheng et al, 2018 ).…”

“…Rab proteins participate in vesicle transport through exocytosis and endocytosis. Current studies have shown that Rab1 protein can regulate the anterograde transport of AT1R from endoplasmic reticulum, through Golgi apparatus and to cell surface, thus promoting vascular remodeling ( Connor et al, 2015 ; Raza et al, 2018 ; Vasile et al, 2020 ). Therefore, we primarily proved that AT1R vesicle transport might be mediated by Rab1 in vascular remodeling in DMCI ( Schöppner et al, 2016 ; Yang et al, 2016 ).…”

Update on Angiotensin II Subtype 2 Receptor: Focus on Peptide and Nonpeptide Agonists

“…The retrospective analysis in the chemical evolution of AT2R peptide agonists by molecular binding modes and affinity estimations with the free energy perturbation method has shown that CG42112A presents a guanidine group on a branched-like structure mimicking the side-chain of Arg 2 in Ang II, which explains its strong affinity to AT2R (Vasile et al, 2020).…”

The SARS-CoV2 - ACE2 link: a physiopathological analysis

“…The Ang II induces its pathological vasoconstrictive, proinflammatory and pro-fibrotic effects via G-protein factors such as the angiotensin II type 1 receptors (AT1R) and angiotensin II type 2 receptors (AT2R) [7]. Previous studies conducted in vitro and in vivo have revealed that vascular overload results in an increased release of Ang II followed by activation of AT1R which induces apoptosis in cardiac cells exposed to increased vascular volumes while the ATR2 is also over expressed after myocardial ischemia [8,9,10].…”