Could DIZE be the answer to COVID-19?

A new strain of coronavirus identified as SARS-CoV-2 causes coronavirus disease-19 (COVID-19) and appeared late in 2019. The World Health Organization (WHO) classified COVID-19 as a public health emergency on 30 January 2020. The disease has been a burden on public health and has had a negative impact on the global economy. On 11 March 2020, the WHO announced it a pandemic. The angiotensin-converting enzyme 2 (ACE2) enzyme is the receptor for SARS-CoV-2 virus entry into the cell [[1]Li W. Moore M.J. Vasilieva N. Sui J. Wong S.K. Berne M.A. Somasundaran M. Sullivan J.L. Luzuriaga K. Greenough T.C. Choe H. Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.Nature. 2003; 426: 450-454Crossref PubMed Scopus (4492) Google Scholar] and speculations have arisen on inhibiting ACE2 activity to treat COVID-19. Here, we comment on targeting COVID-19 via ACE2 activation through a small molecular compound called diminazene aceturate (DIZE). 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The role of ACE2 in normal pulmonary and myocardial physiology is well established, considering ACE2 reduction leads to myocardial [[12]Wang W. Patel V.B. Parajuli N. Fan D. Basu R. Wang Z. Ramprasath T. Kassiri Z. Penninger J.M. Oudit G.Y. Heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease.J. Mol. Med. 2014; 92: 847-858Crossref PubMed Scopus (32) Google Scholar,[13]Moritani T. Iwai M. Kanno H. Nakaoka H. Iwanami J. Higaki T. Ishii E. Horiuchi M. ACE2 deficiency induced perivascular fibrosis and cardiac hypertrophy during postnatal development in mice.J. Am. Soc. Hypertens. 2013; 7: 259-266Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar] and pulmonary disease [[14]Sodhi C.P. Wohlford-Lenane C. Yamaguchi Y. Prindle T. Fulton W.B. Wang S. McCray Jr., P.B. Chappell M. Hackam D.J. Jia H. Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg(9) bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration.Am. J. Physiol. Lung Cell Mol. Physiol. 2018; 314: L17-L31Crossref PubMed Scopus (277) Google Scholar,[15]Chen L.N. Yang X.H. Nissen D.H. Chen Y.Y. Wang L.J. Wang J.H. Gao J.L. Zhang L.Y. Dysregulated renin-angiotensin system contributes to acute lung injury caused by hind-limb ischemia-reperfusion in mice.Shock. 2013; 40: 420-429Crossref PubMed Scopus (54) Google Scholar]. Therefore, it stands to reason that SARS-CoV-2 could be inhibiting ACE2 activity, leading to worsened outcomes. Indeed SARS-Cov-2 virus has a higher affinity to ACE2 than SARS-CoV-1 [[16]Chen Y. Guo Y. Pan Y. Zhao Z.J. Structure analysis of the receptor binding of 2019-nCoV.Biochem. Biophys. Res. Commun. 2020; 525: 135-140Crossref PubMed Scopus (551) Google Scholar]. Recently, opinions based on no evidence have been published suggesting that medications increasing ACE2 activity might worsen outcomes [[17]Fang L. Karakiulakis G. Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?.Lancet Respir. Med. 2020; 8: e21Abstract Full Text Full Text PDF PubMed Scopus (2066) Google Scholar], and that patients on ARBs or ACE inhibitors pose a theoretical risk for worsened disease [[18]Marin G.H. Facts and reflections on COVID-19 and anti-hypertensives drugs.Drug Discov. Ther. 2020; 14: 105-106Crossref PubMed Scopus (23) Google Scholar], and recently the authors have maintained their opinion [[19]Fang L. Karakiulakis G. Roth M. Antihypertensive drugs and risk of COVID-19? - Authors' reply.Lancet Respir. Med. 2020; 8: e28Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar] even after a counterargument [[20]Tignanelli C.J. Ingraham N.E. Sparks M.A. Reilkoff R. Bezdicek T. Benson B. Schacker T. Chipman J.G. Puskarich M.A. Antihypertensive drugs and risk of COVID-19?.Lancet Respir. Med. 2020; 8: e30-e31Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar]. Yet, if true, this opinion would disregard all the scientific data showing a benefit for ACE2 in pathologies. Recently, two articles [[21]Sanchis-Gomar F. Lavie C.J. Perez-Quilis C. Henry B.M. Lippi G. angiotensin-converting enzyme 2 and anti-hypertensives (angiotensin receptor blockers and angiotensin converting enzyme inhibitors) in coronavirus disease 2019 (COVID-19).Mayo Clinic Proceedings. 2020; Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar,[22]Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics.Drug Dev. Res. 2020; (Published March 4 2020): 1-4https://onlinelibrary.wiley.com/doi/abs/10.1002/ddr.21656Google Scholar] clearly pointed to a benefit of using such medications, and that there is no evidence that an increased ACE2 expression would imply an increased risk of infection or outcomes. Indeed, the authors point to elevated cellular levels of angiotensin II, as the main proponent of disease outcomes, and thus removing this peptide from the milieu, via ACE2, could promote disease regression. Therefore, it was proposed that medications aimed at increasing ACE2 expression would reduce, not increase, COVID-19 pathologies. In this regard, we propose that theories based on no evidence, or 'theoretical opinions', should not be treated with the same esteem as theories based on evidence. Such theoretical opinions would render the scientific community akin to following 'educated conspiracy theories', and fall into the logical fallacy 'appeal to authority'. We published a paper on DIZE [[8]Qaradakhi T. Gadanec L.K. McSweeney K.R. Tacey A. Apostolopoulos V. Levinger I. Rimarova K. Egom E.E. Rodrigo L. Kruzliak P. Kubatka P. Zulli A. The potential actions of angiotensin-converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases.Clin. Exp. Pharmacol. Physiol. 2020; 47: 751-758Crossref PubMed Scopus (75) Google Scholar] showing its effect at increasing ACE2 activity. We have also noted that DIZE increases ACE2 protein in blood vessels (manuscript submitted) but whether or not DIZE can directly bind to ACE2 is currently unknown. A recent study shows that soluble ACE2 might bind to SARS-CoV-2 virus, thus blocking its ability to bind to cellular ACE2 [[23]Sun P. Lu X. Xu C. Wang Y. Sun W. Xi J. CD-sACE2 inclusion compounds: an effective treatment for corona virus disease 2019 (COVID-19).J. Med. Virol. 2020; (Published 31 March 2020): 1-3https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25804PubMed Google Scholar] and ACE2 delivered by an adeno-associated viral vector increased angiotensin (1–7) and reduced angiotensin II levels in a mouse model [[24]Rajapaksha I.G. Gunarathne L.S. Asadi K. Cunningham S.C. Sharland A. Alexander I.E. Angus P.W. Herath C.B. Liver-targeted angiotensin converting enzyme 2 therapy inhibits chronic biliary fibrosis in multiple drug-resistant gene 2-Knockout mice.Hepatol Commun. 2019; 3: 1656-1673Crossref PubMed Scopus (32) Google Scholar]. Further evidence suggests that ACE2 activation is critical to balance the pro-apoptotic and anti-apoptotic effects by Ang II and Ang (1–7), respectively, in regulating alveolar epithelial cell survival [[25]Uhal B.D. Li X. Xue A. Gao X. Abdul-Hafez A. Regulation of alveolar epithelial cell survival by the ACE-2/angiotensin 1-7/Mas axis.Am. J. Physiol. Lung Cell Mol. Physiol. 2011; 301: L269-74Crossref PubMed Scopus (99) Google Scholar]. As 83 % of ACE2-expressing cells are alveolar epithelial cells in healthy lung tissue of adult donors, the suggestion to inhibit ACE2 activity in treating COVID-19 might lead to worsened outcomes. Finally, a recent pre-print suggested that DIZE may have the potential to prevent the production of cytokine storm (an inflammatory response) produced in patients with SARS-CoV2 [[26]Labelle J.-P. Using Diminazene Aceturate to Prevent Cytokine Storm Caused by COVID19.2020Google Scholar]. Although anti-virals are being developed and tested [[27]Xia S. Liu M. Wang C. Xu W. Lan Q. Feng S. et al.Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion.Cell Res. 2020; 30: 343-355Crossref PubMed Scopus (940) Google Scholar,[28]Hoffmann M. Kleine-Weber H. Schroeder S. Kruger N. Herrler T. Erichsen S. Schiergens T.S. Herrler G. Wu N.H. Nitsche A. Muller M.A. Drosten C. Pohlmann S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor.Cell. 2020; 181: 271-280Abstract Full Text Full Text PDF PubMed Scopus (13226) Google Scholar], we propose that ACE2 co-therapy could be used to prevent SARS-CoV-2 complications. Tawar Qaradakhi contributed data and contributed to the writing and revision of this editorial. Laura Gadanec contributed data and contributed to the writing and revision of this editorial. John Matsoukas contributed to the writing and revision of this editorial. Vasso Apostolopoulos conceptualized the editorial and contributed to the writing and revision of this editorial. Anthony Zulli conceptualized the editorial and contributed to the writing and revision of this editorial. The authors declare that they have no conflict of interest. No funding was received for the preparation of this editorial.