Interactions between ibuprofen, ACE2, renin‐angiotensin system, and spike protein in the lung. Implications for COVID‐19

SARS-CoV-2 infection is mediated by the binding of its spike protein to the angiotensin-converting enzyme 2 (ACE2), which plays a pivotal role in the renin-angiotensin system (RAS). The study of RAS dysregulation due to SARS-CoV-2 infection is fundamentally important for a better understanding of the pathogenic mechanisms and risk factors associated with COVID-19 coronavirus disease and to design effective therapeutic strategies. In this context, we developed a mathematical model of RAS based on data regarding protein and peptide concentrations; the model was tested on clinical data from healthy normotensive and hypertensive individuals. We used our model to analyze the impact of SARS-CoV-2 infection on RAS, which we modeled through a downregulation of ACE2 as a function of viral load. We also used it to predict the effect of RAS-targeting drugs, such as RAS-blockers, human recombinant ACE2, and angiotensin 1–7 peptide, on COVID-19 patients; the model predicted an improvement of the clinical outcome for some drugs and a worsening for others. Our model and its predictions constitute a valuable framework for in silico testing of hypotheses about the COVID-19 pathogenic mechanisms and the effect of drugs aiming to restore RAS functionality.

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SARS-CoV-2 Receptor and Renin-Angiotensin System Regulation: Impact of Genetics Variants in ACE2 Gene Impact of Genetics Variants in the ACE2 Gene in the Functional Receptor of SARS-CoV-2

Volume 5 - 2020, Issue 9 - September - International Journal of Innovative Science and Research Technology ◽

10.38124/ijisrt20jul268 ◽

2020 ◽

Vol 5 (7) ◽

pp. 489-497

Author(s):

Juliana de Oliveira Cruz ◽

Sandra Mara Bispo Sousa

Keyword(s):

Protein Binding ◽

Genetic Variants ◽

Evolutionary Relationship ◽

Physiological Role ◽

Renin Angiotensin System ◽

Spike Protein ◽

Human Populations ◽

Angiotensin System ◽

Renin Angiotensin ◽

Ace2 Gene

The ACE2 has a physiological role in the regulation of the Renin-Angiotensin System. It is also described your function as a receptor for SARS-CoV-2 and other coronaviruses. Genetic variants in ACE2 are associated with cardiovascular diseases in different human populations and drug response. There is no direct evidence that mutations in ACE2 confer resistance to coronavirus spike protein binding. The evolutionary relationship between spike protein binding and ACE2 is complex. Significant genetic variants are present in ACE2, meanwhile, the evolutionary time of contact of the human ACE2 to the virus is short and, therefore, it did not suffer sufficient selective pressures to offer resistance to viral spike protein binding at the population level. More efforts are needed to identify genetic variants in human ACE2 and other genes, and, consequently, conducting case-control studies to validate these variants and their possible association with infection rates by SARS-CoV-2 and/or clinical outcome.

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Hypothesis: Free SARS-CoV-2 spike protein S1 particles may act as a factor of COVID-19 pathogenesis.

10.31219/osf.io/wp385 ◽

2020 ◽

Author(s):

Andrey Letarov ◽

Vladislav Babenko

Keyword(s):

Angiotensin Ii ◽

Murine Model ◽

Renin Angiotensin System ◽

Spike Protein ◽

Angiotensin System ◽

Renin Angiotensin ◽

Pulmonary Damage ◽

Infected Cells ◽

Ace Activity

The disbalance of the renin-angiotensin system was suggested to play an important role in the pathogenesis of the COVID-19 disease. Previously it has been shown that ACE2 expression in downregulated in the murine model in response to SARS-CoV infection and may be also induced by the recombinant spike protein alone. We hypothesize that the soluble SARS-CoV-2 spike protein S1 subunits shed from the infected cells and from the virions in vivo may bind to the ACE2 receptor and trigger ACE2 downregulation. Decreased ACE2 activity on the background of the constant or increased ACE activity in the lungs may lead to the prevalence of angiotensin II effects over angiotensin(1-7) connected to increased thrombosis, inflammation and pulmonary damage.

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