Role of Angiotensin II in Cardiovascular Diseases: Introducing Bisartans as a Novel Therapy for Coronavirus 2019

Figure 1. AngII/AT1R signaling pathways contribute to the immunopathological features of COVID-19. AngII is produced by the conversion of angiotensinogen from the liver into AngI by the release of renin from the kidney. AngI is metabolized by ACE into AngII, which can bind to the G-protein-coupled AT1R. The interaction of ACE2 with SARS-CoV-2 results in a loss of its functional expression and thus decreases its ability to metabolize AngII into the protective Ang (1–7). This interaction is marked by the excessive activation of AT1R signaling to promote tissue-dependent signal transduction pathways. In VSMCs, AngII/AT1R signaling results in the downstream formation of PLC, leading to the generation of DAG and activation of PKC and IP3. IP3 is then free to release Ca2+ into the cell cytosol, where it initiates vasoconstriction. Additionally, AngII/AT1R signaling can activate various protein kinase signaling pathways (p38-MAPK, JAK-STAT, ERK, and PKC), which are all involved in the pathogenic effects of AngII. This includes AngII-dependent oxidative stress through activation of NOX, resulting in the production of ROS, O2− and H2O2 that can damage cellular components, upregulate NF-κB to induce…

Figure 2. Multifunctional targeting ability of bisartans against SARS-CoV-2 infection and COVID-19 progression. (A) Schematic representation of the interaction between the two anionic tetrazole groups of bisartan with AT1R via salt-bridge bonds (yellow dashed lines) between Arg167 and Tyr35, respectively, to provide overwhelming inhibition of receptor activation by AngII. (B) Binding of the anionic tetrazole groups of bisartan with the Zn2+ active site in ACE2 to prevent viral S-protein interaction and thus disrupt viral entry via ACE2. (C) Docking of one tetrazole group of bisartan to residual Cys145 in the proteo-catalytic site of 3CL-pro to disrupt its catalytic ability to mediate viral replication. Abbreviations: ACE2, angiotensin converting enzyme-2; AT1R, angiotensin type 1 receptor; AngII, angiotensin II; COVID-19, coronavirus 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; S-protein, spike protein; 3Cl-pro, 3-chymotrypsin-like protease. Figure created with biorender.com.