Strengthening CoViD-19 therapy via combinations of RAS modulators

• Published in: Medical hypotheses Vol. 150; p. 110571
• Main Authors: Uzunova, Veselina V., Todev, Angel, Zarkos, Jacqueline, Addai, Daniel, Ananiev, Julian, Rashev, Pavel, Alexandrova, Radostina, Tolekova, Anna
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01-05-2021; The Authors. Published by Elsevier Ltd
• Subjects: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2 - antagonists & inhibitors; AT2 receptor agonists; Combinations of modulators; CoVid-19; COVID-19 - drug therapy; Humans; MAS receptor agonists; Peptide Fragments; Proto-Oncogene Proteins - antagonists & inhibitors; Receptors, G-Protein-Coupled - antagonists & inhibitors; Renin-angiotensin system; Renin-Angiotensin System - drug effects; CoVid-19; MAS receptor agonists; AT2 receptor agonists; Renin-angiotensin system; Combinations of modulators
• ISSN: 0306-9877; 1532-2777
• DOI: 10.1016/j.mehy.2021.110571

Evidence has accumulated that the pathology of CoViD-19 is strongly related to the renin-angiotensin system (RAS). The blockage of the angiotensin converting enzyme 2 (ACE2) by the SARS-CoV-2 virus leads to downstream consequences such as increased vascular tone, extensive fibrosis and pronounced immune reactions. Different approaches to tackle the adverse viral effects by compensating the lost ACE2 function have been suggested. Here, we use an unequal-arm lever model to describe a simplified version of the biased regulation exercised by the angiotensin II and angiotensin-(1–7) hormones, which are the substrate and the product of ACE2, respectively. We reason upon the lever dynamics and its disruptions caused by the virus, and propose that a combination of RAS modulators will most efficiently compensate the imbalance due to the excess of angiotensin II and the scarcity of angiotensin-(1–7). Specifically, we focus on the possible benefits of the simultaneous application of two agents, a MAS-receptor agonist and an angiotensin-II-type-2-receptor agonist. We conjecture that this combination has the potential to introduce a beneficial synergistic action that promotes anti-hypoxic, anti-fibrotic and anti-proliferative effects, thereby improving the clinical management of acute and chronic CoViD-19 pathologies.