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Review
. 2020 Sep 1;6(5):317-325.
doi: 10.1093/ehjcvp/pvaa053.

The mechanistic overview of SARS-CoV-2 using angiotensin-converting enzyme 2 to enter the cell for replication: possible treatment options related to the renin-angiotensin system

Annette Offringa  1 , Roy Montijn  1 , Sandeep Singh  2   3 , Martin Paul  4 , Yigal M Pinto  5 , Sara-Joan Pinto-Sietsma  2   3
Affiliations
Review

The mechanistic overview of SARS-CoV-2 using angiotensin-converting enzyme 2 to enter the cell for replication: possible treatment options related to the renin-angiotensin system

Annette Offringa et al. Eur Heart J Cardiovasc Pharmacother. .

Abstract

The SARS-CoV-2 pandemic is a healthcare crisis caused by insufficient knowledge applicable to effectively combat the virus. Therefore, different scientific discovery strategies need to be connected, to generate a rational treatment which can be made available as rapidly as possible. This relies on a solid theoretical understanding of the mechanisms of SARS-CoV-2 infection and host responses, which is coupled to the practical experience of clinicians that are treating patients. Because SARS-CoV-2 enters the cell by binding to angiotensin-converting enzyme 2 (ACE2), targeting ACE2 to prevent such binding seems an obvious strategy to combat infection. However, ACE2 performs its functions outside the cell and was found to enter the cell only by angiotensin II type 1 receptor (AT1R)-induced endocytosis, after which ACE2 is destroyed. This means that preventing uptake of ACE2 into the cell by blocking AT1R would be a more logical approach to limit entry of SARS-CoV-2 into the cell. Since ACE2 plays an important protective role in maintaining key biological processes, treatments should not disrupt the functional capacity of ACE2, to counterbalance the negative effects of the infection. Based on known mechanisms and knowledge of the characteristics of SARS-CoV we propose the hypothesis that the immune system facilitates SARS-CoV-2 replication which disrupts immune regulatory mechanisms. The proposed mechanism by which SARS-CoV-2 causes disease immediately suggests a possible treatment, since the AT1R is a key player in this whole process. AT1R antagonists appear to be the ideal candidate for the treatment of SARS-CoV-2 infection. AT1R antagonists counterbalance the negative consequences of angiotesnin II and, in addition, they might even be involved in preventing the cellular uptake of the virus without interfering with ACE2 function. AT1R antagonists are widely available, cheap, and safe. Therefore, we propose to consider using AT1R antagonists in the treatment of SARS-CoV-2.

Keywords: Angiotensin receptor blockers; Angiotensin-converting enzyme 2; COVID-19; Coronavirus; Renin–angiotensin–aldosterone system.

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Figures

Figure 1
Figure 1
The RAS system. Coronavirus HCoV-229E binds to the APN receptor to enter the cell. SARS-CoV, NL63, and SARS-CoV-2 use the ACE2 receptor.
Figure 2
Figure 2
Hypothesis of the mechanism of replication of SARS-CoV-2 and treatment aims to prevent virus replication and initiating activation of the adaptive immune response. During inflammation and in the absence of NO, AngII activates the AT1R. AT1R induces cellular uptake of ACE2-bound SARS-CoV-2. Inhibition of AT1R inhibits viral uptake and facilitates AT2R-induced ACE2 expression and subsequent activation of the adaptive immune response.
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