Combination of Angiotensin (1-7) Agonists and Convalescent Plasma as a New Strategy to Overcome Angiotensin Converting Enzyme 2 (ACE2) Inhibition for the Treatment of COVID-19

Abstract

Coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the most concerning health problem worldwide. SARS-CoV-2 infects cells by binding to angiotensin-converting enzyme 2 (ACE2). It is believed that the differential response to SARS-CoV-2 is correlated with the differential expression of ACE2. Several reports proposed the use of ACE2 pharmacological inhibitors and ACE2 antibodies to block viral entry. However, ACE2 inhibition is associated with lung and cardiovascular pathology and would probably increase the pathogenesis of COVID-19. Therefore, utilizing ACE2 soluble analogs to block viral entry while rescuing ACE2 activity has been proposed. Despite their protective effects, such analogs can form a circulating reservoir of the virus, thus accelerating its spread in the body. Levels of ACE2 are reduced following viral infection, possibly due to increased viral entry and lysis of ACE2 positive cells. Downregulation of ACE2/Ang (1-7) axis is associated with Ang II upregulation. Of note, while Ang (1-7) exerts protective effects on the lung and cardiovasculature, Ang II elicits pro-inflammatory and pro-fibrotic detrimental effects by binding to the angiotensin type 1 receptor (AT1R). Indeed, AT1R blockers (ARBs) can alleviate the harmful effects associated with Ang II upregulation while increasing ACE2 expression and thus the risk of viral infection. Therefore, Ang (1-7) agonists seem to be a better treatment option. Another approach is the transfusion of convalescent plasma from recovered patients with deteriorated symptoms. Indeed, this appears to be promising due to the neutralizing capacity of anti-COVID-19 antibodies. In light of these considerations, we encourage the adoption of Ang (1-7) agonists and convalescent plasma conjugated therapy for the treatment of COVID-19 patients. This therapeutic regimen is expected to be a safer choice since it possesses the proven ability to neutralize the virus while ensuring lung and cardiovascular protection through modulation of the inflammatory response.

Quantifying Renin-Angiotensin-System Alterations in COVID-19

“…Preclinical evidence suggests that not only rhACE2 but also the exogenous administration of Ang-(1-7) peptide can improve severe clinical ARDS conditions such as low oxygenation and high inflammation status [113,114]. Thus, administration of Ang-(1-7) or Ang-(1-7) agonists has been suggested to mitigate SARS-CoV-2 infections by boosting the anti-inflammatory response via MASR activation [10,115].…”

Depressive and Neurocognitive Disorders in the Context of the Inflammatory Background of COVID-19

“…ACE2 is widely expressed on the surface of many organ cells, especially in the lungs and intestine, as well as in the cardiovascular system, kidneys, adipose tissue and central nervous system. That is why we observe a range of symptoms in the course of COVID-19, from the symptoms typical of the respiratory and digestive system, to thrombotic events, kidney failure and a number of neuropsychiatric symptoms [80,81]. The appropriate level of ACE2 is necessary for the proper maintenance of homeostasis in cells.…”

Developing Cytokine Storm-Sensitive Therapeutic Strategy in COVID-19 Using 8P9R Chimeric Peptide and Soluble ACE2

“…Then, Ang-(1-7) binds to Mas receptors and exerts its positive effects, including anti-inflammatory and anti-fibrotic effects (South et al, 2020). Ang-(1-7) by acting via the Mas receptor inhibits NF-κB signaling pathway and interferes with inflammation (Issa et al, 2021). Ang-(1-7) reduces expression of pro-inflammatory cytokines, promotes anti-inflammatory M2 phenotype, and reduces pro-inflammatory M1 phenotype (de Carvalho Santuchi et al, 2019;Magalhaes et al, 2020).…”