Receptor Interactions of Angiotensin II and Angiotensin Receptor Blockers-Relevance to COVID-19.

Graham J Moore,Konstantinos Kelaidonis,Vasso Apostolopoulos,Jose M Pires,Anthony Zulli,John M Matsoukas,Laura Kate Gadanec

doi:10.3390/biom11070979

Graham J Moore, Konstantinos Kelaidonis + Show 5 more

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https://doi.org/10.3390/biom11070979

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Abstract

Angiotensin II (Ang II) may contain a charge relay system (CRS) involving Tyr/His/carboxylate, which creates a tyrosinate anion for receptor activation. Energy calculations were carried out to determine the preferred geometry for the CRS in the presence and absence of the Arg guanidino group occupying position 2 of Ang II. These findings suggest that Tyr is preferred over His for bearing the negative charge and that the CRS is stabilized by the guanidino group. Recent crystallography studies provided details of the binding of nonpeptide angiotensin receptor blockers (ARBs) to the Ang II type 1 (AT1) receptor, and these insights were applied to Ang II. A model of binding and receptor activation that explains the surmountable and insurmountable effects of Ang II analogues sarmesin and sarilesin, respectively, was developed and enabled the discovery of a new generation of ARBs called bisartans. Finally, we determined the ability of the bisartan BV6(TFA) to act as a potential ARB, demonstrating similar effects to candesartan, by reducing vasoconstriction of rabbit iliac arteries in response to cumulative doses of Ang II. Recent clinical studies have shown that Ang II receptor blockers have protective effects in hypertensive patients infected with SARS-CoV-2. Therefore, the usage of ARBS to block the AT1 receptor preventing the binding of toxic angiotensin implicated in the storm of cytokines in SARS-CoV-2 is a target treatment and opens new avenues for disease therapy.

Highlights

Introduction published maps and institutional affilThe octapeptide angiotensin II (Ang II) (DRVYIHPF) acts on the Ang II type 1 (AT1)receptors in a variety of vascular smooth muscle tissues, eliciting a contractile response.This results in an increase in blood pressure
In accordance with this general concept, fluorescence lifetime studies on Ang II in receptorsimulating environments have demonstrated the presence of tyrosinate anions that become increasingly stabilized as the dielectric constant of the environment decreases [2]
The introduction of the Arg side chain into the network alters the geometry of the charge relay interaction and has a stabilizing influence on the folded compact charge transfer conformation

Summary

Introduction

Receptors in a variety of vascular smooth muscle tissues, eliciting a contractile response. This results in an increase in blood pressure. Several lines of evidence suggest that the interaction of Ang II with its receptors involves a charge relay mechanism (CRS) [1]. Folding of the peptide in the hydrophobic membrane receptor environment brings together the Tyr, His, and Phe side chains of the peptide in a concerted interaction. This results in the transfer of the negative charge at the C-terminal carboxylate to the Tyr hydroxyl group via the His imidazole (Figure 1), which is analogous to serine proteases. (Sar Tyr(Me)4)Ang II (sarmesin) is a surmountable competitive antagonist, illustrating the role of the Tyr hydroxyl for agonist iations

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