Treatment Options Available for COVID-19 and an Analysis on Possible Role of Combination of rhACE2, Angiotensin (1-7) and Angiotensin (1-9) as Effective Therapeutic Measure

Abstract

Corona virus disease (COVID-19), caused by SARS-CoV-2, is rapidly spreading all around the world and is posing a threat to mankind. Since SARS-CoV-2 is a novel virus, little is known about it and no effective drug is available for its treatment. While many drugs are being evaluated, an effective therapeutic measure is still lacking. SARS-CoV-2 like SARS-CoV binds with angiotensin-converting enzyme 2 (ACE2) present on human cells. SARS-CoV has been found to downregulate ACE2 and SARS-CoV-2 infection has been found to be associated with increased level of Angiotensin II. Based on these facts, we presume that SARS-CoV-2 like SARS-CoV downregulates ACE2, and in absence/reduced activity of ACE2, level of angiotensin (1-7) and angiotensin (1-9) is decreased while that of angiotensin II is increased and increased level of angiotensin II has been found to correlate with lung injury and viral load. We presume that restoration of normal functioning of renin-angiotensin system with recombinant human angiotensin-converting enzyme 2 (rhACE2), angiotensin (1-7) and angiotensin (1-9) may be an effective therapeutic measure but studies will be required to test this hypothesis and explore its possible role in treatment of COVID-19. Keywords COVID-19. Angiotensin-converting enzyme 2. rhACE2. SARS-CoV-2. Angiotensin This article is part of the Topical Collection on Covid-19

Potential detrimental role of soluble ACE2 in severe COVID‐19 comorbid patients

“… 22 , 23 Several studies have reported the beneficial and preventive role of therapeutic sACE2 in COVID‐19 21 ,. 24–28 Surprisingly, clinical data suggest that patients with low mACE2 and high sACE2 faced more disease severity and fatality 25 ,. 28 This contrasts with the protective role of therapeutic sACE2 claimed in literature.…”

The renin-angiotensin system and specifically angiotensin-converting enzyme 2 as a potential therapeutic target in SARS-CoV-2 infections

“…Come già descritto, l'ACE-2 è il recettore di ingresso cellulare della SARS-CoV-2, ed è anche un componente chiave del RAS. Pertanto, una piena comprensione della correlazione tra ACE-2 e SARS-CoV-2 sarebbe di fondamentale importanza per agire con strategie di intervento farmacologico mirate (Ferrara and Vitiello 2020 ; Vitiello and Ferrara 2021d ; Ferrara and Vitiello 2021b ; Muslim et al 2020 ). Tuttavia, sebbene l'ACE-2 sia stato identificato come recettore della SARS-CoV-2, potrebbero esserci altri co-recettori della SARS-CoV-2 ancora da scoprire (Muslim et al 2020 ).…”

“…Pertanto, una piena comprensione della correlazione tra ACE-2 e SARS-CoV-2 sarebbe di fondamentale importanza per agire con strategie di intervento farmacologico mirate (Ferrara and Vitiello 2020 ; Vitiello and Ferrara 2021d ; Ferrara and Vitiello 2021b ; Muslim et al 2020 ). Tuttavia, sebbene l'ACE-2 sia stato identificato come recettore della SARS-CoV-2, potrebbero esserci altri co-recettori della SARS-CoV-2 ancora da scoprire (Muslim et al 2020 ). Ciò solleva ulteriori importanti implicazioni per i bersagli terapeutici della SARS-CoV-2 (Marovich et al 2020 ; Vitiello et al 2021d ; Singh et al 2021 ).…”

“…Treatment with a soluble recombinant human form of ACE2 (rhACE2) could prove useful as a trap effect for circulating SARS-CoV2 and decrease viral load and hinder infection (Monteil et al 2020 ). Administration of recombinant soluble human ACE2 has shown good efficacy in subjects with acute respiratory distress syndrome (ARDS) (Muslim et al 2020 ). From a molecular pharmacological point of view, administration of rhACE2 activates the Ang 1–7 and Ang 1–9 synthesis pathway of the RAS system (non-classical pathway) by decreasing Ang II levels with a tendency to lower the concentration of proinflammatory cytokines (Gaddam et al 2014 ).…”

Developing new drugs that activate the protective arm of the renin–angiotensin system as a potential treatment for respiratory failure in COVID-19 patients

“…Importantly, these excessive levels of Ang-II are linearly associated with SARS-Cov-2 viral load and severity of lung injury during COVID-19 13 , 14 . In addition, the plasma levels of Ang-(1–7) and potentially those of Ang-1–9 [15] are significantly lower in COVID-19 patients than in healthy controls, and these levels are particularly low in COVID-19 patients who are admitted to ICUs. As a consequence, a general imbalance between the ‘harmful’ and ‘protective’ arms of the RAS, resulting from excessive activation of AT1R and limited activation of AT2R and MasR, has been proposed, and this hypothesis is supported by the clinical picture reported in COVID-19 patients [12] .…”