Diminazene Aceturate Reduces Angiotensin II Constriction and Interacts with the Spike Protein of Severe Acute Respiratory Syndrome Coronavirus 2

Abstract

Diminazene aceturate (DIZE) is a putative angiotensin-converting enzyme 2 (ACE2) activator and angiotensin type 1 receptor antagonist (AT1R). Its simple chemical structure possesses a negatively charged triazene segment that is homologous to the tetrazole of angiotensin receptor blockers (ARB), which explains its AT1R antagonistic activity. Additionally, the activation of ACE2 by DIZE converts the toxic octapeptide angiotensin II (AngII) to the heptapeptides angiotensin 1–7 and alamandine, which promote vasodilation and maintains homeostatic balance. Due to DIZE’s protective cardiovascular and pulmonary effects and its ability to target ACE2 (the predominant receptor utilized by severe acute respiratory syndrome coronavirus 2 to enter host cells), it is a promising treatment for coronavirus 2019 (COVID-19). To determine DIZE’s ability to inhibit AngII constriction, in vitro isometric tension analysis was conducted on rabbit iliac arteries incubated with DIZE or candesartan and constricted with cumulative doses of AngII. In silico docking and ligand interaction studies were performed to investigate potential interactions between DIZE and other ARBs with AT1R and the spike protein/ACE2 complex. DIZE, similar to the other ARBs investigated, was able to abolish vasoconstriction in response to AngII and exhibited a binding affinity for the spike protein/ACE2 complex (PDB 6LZ6). These results support the potential of DIZE as a treatment for COVID-19.

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

“…Additionally, the authors report that these results were not supported in both human renal and intestinal cell lines [171]. Moreover, agents that upregulate ACE2 have gained notoriety as potential COVID-19 treatments, as they may reduce the pathogenic effect of AngII, reactivate ACE2, and ultimately restore RAS balance [142,172,173]. For example, our group has recently shown that the putative ACE2 activator, diminazene aceturate, can interact with the SARS-CoV-2 S-protein and reduce AngII-mediated constriction in rabbit iliac arteries [172,173].…”

“…Moreover, agents that upregulate ACE2 have gained notoriety as potential COVID-19 treatments, as they may reduce the pathogenic effect of AngII, reactivate ACE2, and ultimately restore RAS balance [142,172,173]. For example, our group has recently shown that the putative ACE2 activator, diminazene aceturate, can interact with the SARS-CoV-2 S-protein and reduce AngII-mediated constriction in rabbit iliac arteries [172,173]. To date, there is no conclusive evidence regarding the increased risk of infectivity, morbidity, or mortality among RAS inhibitor users.…”

Computational and Enzymatic Studies of Sartans in SARS-CoV-2 Spike RBD-ACE2 Binding: The Role of Tetrazole and Perspectives as Antihypertensive and COVID-19 Therapeutics

“…The imbalance in the renin-angiotensin system (excess of toxic angiotensin II against beneficial heptapeptides A(1-7), Alamantine) is responsible for hypertension and COVID-19. ARBs upregulate ACE2 which upgrades angiotensin II are proven to be beneficial against SARS-CoV-2 [63,64]. Scheme 1 shows the synthetic scheme for bisartan imidazole-based ligands Co4, Co6, Co8, and Co10.…”

“…For this study, the crystal structures of the proteins were extracted by the Protein Data Bank. These results were compared to candesartan, a known ARB, from our previous study, as well as valsartan, olmesartan, and eprosartan [63]. The X-ray crystal structures of the spike receptor domain complexed with ACE2 (PDB ID: 6LZG) were downloaded from the RCSB PDB (Protein Data Bank) database [70,71].…”