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Review
. 2021 Feb 8:20:252-275.
doi: 10.17179/excli2021-3412. eCollection 2021.

Insights into the actions of angiotensin-1 receptor (AT1R) inverse agonists: Perspectives and implications in COVID-19 treatment

Luana Heimfarth  1 , Mario Adriano Dos Santos  2 , José Augusto Barreto-Filho  3 , André Sales Barreto  4 , Fabrício Nunes Macedo  5 , Adriano Antunes de Souza Araújo  6 , Paulo Martins-Filho  3 , Marcus Tullius Scotti  7 , Luciana Scotti  7 , Lucindo José Quintans-Júnior  1
Affiliations
Review

Insights into the actions of angiotensin-1 receptor (AT1R) inverse agonists: Perspectives and implications in COVID-19 treatment

Luana Heimfarth et al. EXCLI J. .

Abstract

New coronavirus SARS-CoV-2 (COVID-19) has caused chaos in health care systems. Clinical manifestations of COVID-19 are variable, with a complex pathophysiology and as yet no specific treatment. It has been suggested that the renin-angiotensin-aldosterone system has a possible role in the severity of cases and the number of deaths. Our hypothesis is that drugs with inverse agonist effects to the angiotensin-1 receptor can be promising tools in the management of patients with COVID-19, possibly avoiding complications and the poor evolution in some cases. Any risk factors first need to be identified, and the most appropriate time to administer the drugs during the course of the infection also needs to be established. Several angiotensin receptor blockers (ARB) have a favorable profile and are important candidates for the treatment of COVID-19. In this review we discussed a set of compounds with favorable profile for COVID-19 treatment, including azilsartan, candesartan, eprosartan, EXP3174, olmesartan, telmisartan, and valsartan. They are effective as inverse agonists and could reduce the "cytokine storm" and reducing oxidative stress. As COVID-19 disease has several evolution patterns, the effectiveness of ARB therapy would be related to infection "timing", patient risk factors, previous use of ARBs, and the specific molecular effects of an ARB. However, controlled studies are needed to identify whether ARBs are beneficial in the treatment of patients with COVID-19.

Keywords: SARS-CoV-2; angiotensin-converting enzyme; drugs; renin-angiotensin-aldosterone system.

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Figures

Table 1
Table 1. AT1 inverse agonist pharmacological effects
Table 2
Table 2. AT1 inverse agonist molecular mechanism
Figure 1
Figure 1. Schematic representation of AT1 agonist, AT1-antagonist and AT1-inverse agonist biological response
Figure 2
Figure 2. Chemical structures of AT1-inverse agonists
Figure 3
Figure 3. Telmisartan interactions in the binding cavity of the AT1 receptor from the docking study
See this image and copyright information in PMC

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