Comparative evaluation of biased agonists Sarcosine¹, d‐Alanine⁸‐Angiotensin (Ang) II (SD Ang II) and Sarcosine¹, Isoleucine⁸‐Ang II (SI Ang II) and their radioiodinated congeners binding to rat liver membrane AT₁ receptors

Abstract

Angiotensin II analogue and β‐arrestin biased agonist TRV027 (Sarcosine 1 , d ‐Alanine 8 ‐Angiotensin (Ang) II; SD Ang II), developed by Trevena, Inc. in the early 2010s, brought hopes of a novel treatment for cardiovascular diseases, due to its ability to simultaneously cause signaling through the β‐arrestin signaling pathway, while antagonizing the pathophysiological effects of Ang II mediated by the AT 1 receptor G protein signaling cascades. However, a phase II clinical trial of this agent revealed no significant benefit compared to placebo treatment. Using 125 I‐Sarcosine 1 , Isoleucine 8 ‐Ang II ( 125 I‐SI Ang II) radioligand receptor competition binding assays, we assessed the relative affinity of TRV027 compared to SI Ang II for liver AT 1 receptors. We also compared radioiodinated TRV027 ( 125 I‐SD Ang II) binding affinity for liver AT 1 receptors with 125 I‐SI Ang II. We found that despite its anticipated gain in metabolic stability, TRV027 and 125 I‐SD Ang II had reduced affinity for the AT 1 receptor compared with SI Ang II and 125 I‐SI Ang II. Additionally, male–female comparisons showed that females have a higher AT 1 receptor density, potentially attributed to tissue‐dependent estrogen and progesterone effects. Peptide drugs have become more popular over the years due to their increased bioavailability, fast onset of action, high specificity, and low toxicity. Even though Trevena®'s biased agonist peptide TRV027 offered greater stability and potency compared to earlier AT 1 R biased agonists, it failed its phase II clinical trial in 2016. Further refinements to AT 1 R biased agonist peptides to improve affinity, as seen with SI Ang II, with better stability and bioavailability, has the potential to achieve the anticipated biased agonism.

Insights Into the Role of Angiotensin-II AT 1 Receptor-Dependent β-Arrestin Signaling in Cardiovascular Disease

“…29 Studies comparing the binding efficacy of biased ligands including TRV027 to AT 1 R in male and female rat liver have been reported. 30 It remains unclear if this is due to sex-mediated difference in the level of AT 1 R or due to difference in the levels of G-coupled receptor kinases, which may be regulated differentially in males and females and are required to phosphorylate the C terminal tail of GPCRs to recruit β-arrestins. 30,31 Indeed, this is important as there are substantial differences in the mechanisms controlling BP by sex.…”

“…30 It remains unclear if this is due to sex-mediated difference in the level of AT 1 R or due to difference in the levels of G-coupled receptor kinases, which may be regulated differentially in males and females and are required to phosphorylate the C terminal tail of GPCRs to recruit β-arrestins. 30,31 Indeed, this is important as there are substantial differences in the mechanisms controlling BP by sex. 32 AT 1 R-β-ARRESTIN SIGNALING AND HEART FAILURE β-arrestins play an important role in normal cardiac physiology as mice carrying global deletion of Arrb1 or Arrb2, the genes encoding β-arrestin-1 and β-arrestin-2, respectively, exhibit low stroke volume and decreased length-dependent force activation.…”