Preprint Brief Report Version 2 This version is not peer-reviewed

The Rational for Administration of ACE2 Pathway Inhibitors in Patients Infected by SARS-CoV-2: Devising an Administration Strategy

Version 1 : Received: 19 March 2020 / Approved: 23 March 2020 / Online: 23 March 2020 (06:29:42 CET)
Version 2 : Received: 23 March 2020 / Approved: 24 March 2020 / Online: 24 March 2020 (06:47:18 CET)

How to cite: Zamai, L. The Rational for Administration of ACE2 Pathway Inhibitors in Patients Infected by SARS-CoV-2: Devising an Administration Strategy. Preprints 2020, 2020030338 (doi: 10.20944/preprints202003.0338.v2). Zamai, L. The Rational for Administration of ACE2 Pathway Inhibitors in Patients Infected by SARS-CoV-2: Devising an Administration Strategy. Preprints 2020, 2020030338 (doi: 10.20944/preprints202003.0338.v2).

Abstract

The article describes the rational for inhibition of the angiotensin-converting enzyme 2 (ACE2) pathways as specific targets in patients infected by SARS-CoV-2. Making use of a large quantity of published reports in which human/rodent ACE2 pathway inhibitors were administered in vivo, I have hypothesized a possible therapeutic pharmacological intervention through an inhibition strategy of ACE2 pathway for SARS-CoV-2 patients who are suffering from critical, advanced and untreatable stages of the disease.

Supplementary and Associated Material

Subject Areas

Severe Acute Respiratory Syndrome Coronavirus-2; (soluble) ACE2; eosinophil; asthma; IL-10; IL-6; Lung fibrosis; Angiotensin; hypoxia; infarction; hypertension; hypercapnic acidosis; hypoxia; infarction; hypertension

Comments (2)

Comment 1
Received: 24 March 2020
Commenter: Loris ZAMAI
Commenter's Conflict of Interests: Author
Comment: The paper has been improved and possible therapies for SARS CoV-2 patients were added
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Comment 2
Received: 28 March 2020
Commenter: Robson A S Santos
The commenter has declared there is no conflict of interests.
Comment: The main hypothesis of this manuscript is not correct and based in biased information. For example, the heptapetide angiotensin-(1-7) has many beneficial effects in body but the authors stated that it produces deleterious effecs. Actually t is appealing to propose and test the hypothesis that activation of Mas receptor by angiotensin-(1-7) or selective compounds such AVE0091 would have beneficial effects in Covid 19. After the viral infection ACE2 is internalized loosing the capacity to form angiotensin-(1-7). In this condition administration of exogenous Ang-(1-7) could be beneficial for the patients.
Use of soluble recombinant ACE2 or inhibitors of the enzyme could be a rational try, however this would be feasible in the very beginning of the infection or as a preventive measure, which would be economically very difficult. The authors should re-think their hypothesis.
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Response 1 to Comment 2
Received: 30 March 2020
Commenter: Loris ZAMAI
The commenter has declared there is no conflict of interests.
Comment: Comment: The main hypothesis of this manuscript is not correct and based in biased information. For example, the heptapetide angiotensin-(1-7) has many beneficial effects in body but the authors stated that it produces deleterious effecs.

Reply: In the text it is stated:
"Most of the experiments show that increased ACE2 activity leads to beneficial effects; however, they were performed using models in which its “antagonist“ (ACE) pathway was upregulated, therefore balancing an unbalanced situation. What does it happen in models in which the opposite occurs?'''

Actually t is appealing to propose and test the hypothesis that activation of Mas receptor by angiotensin-(1-7) or selective compounds such AVE0091 would have beneficial effects in Covid 19. After the viral infection ACE2 is internalized loosing the capacity to form angiotensin-(1-7). In this condition administration of exogenous Ang-(1-7) could be beneficial for the patients.

Reply: The clinical picture (in particular eosinopenia, hypotension, IL-10) suggests a hyperactivation of ACE2/Ang (1-7)/Mas receptor pathway, probably due to shedding (not internalization, please see references 8 and 9) of active forms of soluble ACE2. AVE0091 induces IL-10 upregulation typically upregulated in SARS-CoV-2 patients. I don’t think it is a good idea to use it.

Use of soluble recombinant ACE2 or inhibitors of the enzyme could be a rational try, however this would be feasible in the very beginning of the infection or as a preventive measure, which would be economically very difficult. The authors should re-think their hypothesis.

Reply: I have stated that my approach is intended only for patients that are already infected with advanced stages of SARS disease, not for prevention of viral entry, that means for people that are dying here in Italy!
Thanks for your critics and suggestions that help me to clarify my point. I am waiting for further comment/critics
All the best
Loris

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