Review Article
 

Mechanisms of COVID-19 Entry into the Cell: Potential Therapeutic Approaches Based on Virus Entry Inhibition in COVID-19 Patients with Underlying Diseases

Therapeutic Approaches Based on SARS-COV-2 Entry Inhibition

Abstract

The Coronavirus disease 2019 (COVID-19) virus spread from Wuhan, China, in 2019 and is spreading rapidly around the world. COVID-19 victims are almost associated with cardiovascular disease, high blood pressure, diabetes, and other underlying diseases. Concerning the high prevalence of these disorders, widespread mortality threatens global society, and its fatality rate may increase with increasing COVID-19 prevalence in countries with older populations. Therefore, evaluating patients' clinical status with severe COVID-19 infection and their medical history can help manage treatment. Currently, one of the considered treatments is angiotensin-converting enzyme 2 (ACE2) inhibition. This study investigated virus entry mechanisms through membrane receptors, their role in the pathogenesis of COVID-19 and underlying diseases, and treatment methods based on the viral entrance inhibition. According to existing studies, inhibition of ACE2 can increase oxidative stress, inflammation, fibrosis and ultimately exacerbate underlying diseases such as cardiovascular disease, kidney disease, diabetes, and hypertension in individuals with COVID-19. The ACE2 inhibition is not suitable for patients with COVID-19 with underlying diseases, but it seems that the recombinant ACE2 solution is more appropriate for inhibiting the virus in these patients if hypotension would be monitored.

1. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-13.
2. Dang Z, Su S, Jin G, Nan X, Ma L, Li Z, et al. Tsantan Sumtang attenuated chronic hypoxia-induced right ventricular structure remodeling and fibrosis by equilibrating local ACE-AngII-AT1R/ACE2-Ang1-7-Mas axis in rat. J Ethnopharmacol. 2020;250:112470.
3. Chan JF-W, Kok K-H, Zhu Z, Chu H, To KK-W, Yuan S, et al. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect. 2020;9(1):221-36.
4. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. Jama. 2020;323(11):1061-9.
5. Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN. Cardiovascular disease, drug therapy, and mortality in Covid-19. N Engl J Med. 2020.
6. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. Jama. 2020.
7. Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270-3.
8. Abazari O, Shafaei Z, Divsalar A, Eslami-Moghadam M, Ghalandari B, Saboury AA. Probing the biological evaluations of a new designed Pt (II) complex using spectroscopic and theoretical approaches: Human hemoglobin as a target. J Biomol Struct Dyn. 2016;34(5):1123-31.
9. White JM, Whittaker GR. Fusion of enveloped viruses in endosomes. Traffic. 2016;17(6):593-614.
10. Ibrahim IM, Abdelmalek DH, Elshahat ME, Elfiky AA. COVID-19 spike-host cell receptor GRP78 binding site prediction. J Infect. 2020.
11. Allam L, Ghrifi F, Mohammed H, El Hafidi N, El Jaoudi R, El Harti J, et al. Targeting the GRP78-Dependant SARS-CoV-2 Cell Entry by Peptides and Small Molecules. Bioinform Biol Insights. 2020;14:1177932220965505.
12. Bailly C, Waring MJ. Pharmacological effectors of GRP78 chaperone in cancers. Biochem Pharmacol. 2019;163:269-78.
13. Rayner JO, Roberts RA, Kim J, Poklepovic A, Roberts JL, Booth L, et al. AR12 (OSU-03012) suppresses GRP78 expression and inhibits SARS-CoV-2 replication. Biochem Pharmacol. 2020;182:114227.
14. Ulrich H, Pillat MM. CD147 as a target for COVID-19 treatment: suggested effects of azithromycin and stem cell engagement. Stem Cell Rev Rep. 2020:1-7.
15. Kaul D. An Overview of Coronaviruses including the SARS-2 Coronavirus–Molecular Biology, Epidemiology and Clinical Implications. Curr Med Res Pract. 2020.
16. Sorbera L, Graul A, Dulsat C. Taking aim at a fast-moving target: targets to watch for SARS-CoV-2 and COVID-19. Drugs Future. 2020;45(4).
17. Chen Z, Mi L, Xu J, Yu J, Wang X, Jiang J, et al. Function of HAb18G/CD147 in invasion of host cells by severe acute respiratory syndrome coronavirus. J Infect Dis. 2005;191(5):755-60.
18. Abazari O, Divsalar A, Ghobadi R. Inhibitory effects of oxali-Platin as a chemotherapeutic drug on the function and structure of bovine liver catalase. J Biomol Struct Dyn. 2020;38(2):609-15.
19. Nigro P, Pompilio G, Capogrossi M. Cyclophilin A: a key player for human disease. Cell Death Dis. 2013;4(10):e888-e.
20. Su H, Yang Y. The roles of CyPA and CD147 in cardiac remodelling. Exp Mol Pathol. 2018;104(3):222-6.
21. Grass GD, Toole BP. How, with whom and when: an overview of CD147-mediated regulatory networks influencing matrix metalloproteinase activity. Biosci Rep. 2016;36(1).
22. Hahn JN, Kaushik DK, Yong VW. The role of EMMPRIN in T cell biology and immunological diseases. J Leukoc Biol. 2015;98(1):33-48.
23. Kosugi T, Maeda K, Sato W, Maruyama S, Kadomatsu K. CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint.Nephrol Dial Transplant. 2015;30(7):1097-103.
24. Jin R, Xiao AY, Chen R, Granger DN, Li G. Inhibition of CD147 (cluster of differentiation 147) ameliorates acute ischemic stroke in mice by reducing thromboinflammation. Stroke. 2017;48(12):3356-65.
25. Tanaka Y, Sato Y, Sasaki T. Suppression of coronavirus replication by cyclophilin inhibitors. Viruses. 2013;5(5):1250-60.
26. Chiu P-F, Su S-L, Tsai C-C, Wu C-L, Kuo C-L, Kor C-T, et al. Cyclophilin A and CD147 associate with progression of diabetic nephropathy. Free Radic Res. 2018;52(11-12):1456-63.
27. Musavi H, Abazari O, Barartabar Z, Kalaki-Jouybari F, Hemmati-Dinarvand M, Esmaeili P, et al. The benefits of Vitamin D in the COVID-19 pandemic: biochemical and immunological mechanisms. Arch Physiol Biochem. 2020:1-9.
28. Brojakowska A, Narula J, Shimony R, Bander J. Clinical Implications of SARS-Cov2 Interaction with Renin Angiotensin System. JACC. 2020.
29. Imai Y, Kuba K, Penninger JM. The discovery of angiotensin‐converting enzyme 2 and its role in acute lung injury in mice. Exp Physiol. 2008;93(5):543-8.
30. Hashimoto T, Perlot T, Rehman A, Trichereau J, Ishiguro H, Paolino M, et al. ACE2 links amino acid malnutrition to microbial ecology and intestinal inflammation. Nature. 2012;487(7408):477-81.
31. Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol. 2020;5(4):562-9.
32. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506.
33. Fan C, Li K, Ding Y, Lu WL, Wang J. ACE2 expression in kidney and testis may cause kidney and testis damage after 2019-nCoV infection. MedRxiv. 2020.
34. Walls AC, Park Y-J, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell. 2020.
35. Zhang C, Shi L, Wang F-S. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol. 2020.
36. Chai X, Hu L, Zhang Y, Han W, Lu Z, Ke A, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. bioRxiv. 2020.
37. Cheng H, Wang Y, Wang GQ. Organ‐protective Effect of Angiotensin‐converting Enzyme 2 and its Effect on the Prognosis of COVID‐19. JMed Virol. 2020.
38. Mendoza-Torres E, Oyarzún A, Mondaca-Ruff D, Azocar A, Castro PF, Jalil JE, et al. ACE2 and vasoactive peptides: novel players in cardiovascular/renal remodeling and hypertension. Ther Adv Cardiovasc Dis. 2015;9(4):217-37.
39. Niu M-J, Yang J-K, Lin S-S, Ji X-J, Guo L-M. Loss of angiotensin-converting enzyme 2 leads to impaired glucose homeostasis in mice. Endocrine. 2008;34(1-3):56-61.
40. Burrell LM, Burchill L, Dean RG, Griggs K, Patel SK, Velkoska E. Chronic kidney disease: cardiac and renal angiotensin‐converting enzyme (ACE) 2 expression in rats after subtotal nephrectomy and the effect of ACE inhibition. Exp Physiol. 2012;97(4):477-85.
41. Ramchand J, Patel SK, Srivastava PM, Farouque O, Burrell LM. Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease. PLoS One. 2018;13(6):e0198144.
42. Walters TE, Kalman JM, Patel SK, Mearns M, Velkoska E, Burrell LM. Angiotensin converting enzyme 2 activity and human atrial fibrillation: increased plasma angiotensin converting enzyme 2 activity is associated with atrial fibrillation and more advanced left atrial structural remodelling. Ep Europace. 2017;19(8):1280-7.
43. Asadi A, Nezhad DY, Javazm AR, Khanicheragh P, Mashouri L, Shakeri F, et al. In vitro Effects of Curcumin on Transforming Growth Factor-β-mediated Non-Smad Signaling Pathway, Oxidative Stress, and Pro‐inflammatory Cytokines Production with Human Vascular Smooth Muscle Cells.
Iran J Allergy Asthma Immunol. 2020:84-93.
44. Ramchand J, Patel SK, Kearney LG, Matalanis G, Farouque O, Srivastava PM, et al. Plasma ACE2 activity predicts mortality in aortic stenosis and is associated with severe myocardial fibrosis. JACC Cardiovasc Imaging. 2020;13(3):655-64.
45. Richards EM, Raizada MK. ACE2 and pACE2: a pair of aces for pulmonary arterial hypertension treatment? : Am Thorac Soc; 2018.
46. Dai H, Gong Y, Xiao Z, Guang X, Yin X. Decreased levels of serum Angiotensin-(1-7) in patients with pulmonary arterial hypertension due to congenital heart disease.Int J Cardiol . 2014;176(3):1399.
47. Shao M, Wen Z-B, Yang H-H, Zhang C-Y, Xiong J-B, Guan X-X, et al. Exogenous angiotensin (1-7) directly inhibits epithelial-mesenchymal transformation induced by transforming growth factor-β1 in alveolar epithelial cells. Biomed Pharmacother. 2019;117:109193.
48. Sharma N, Anders H-J, Gaikwad AB. Fiend and friend in the renin angiotensin system: an insight on acute kidney injury. Biomed Pharmacother. 2019;110:764-74.
49. Verma A, Xu K, Du T, Zhu P, Liang Z, Liao S, et al. Expression of human ACE2 in Lactobacillus and beneficial effects in diabetic retinopathy in mice.Mol Ther Methods Clin Dev. 2019;14:161-70.
50. Santos RAS, Sampaio WO, Alzamora AC, Motta-Santos D, Alenina N, Bader M, et al. The ACE2/angiotensin-(1–7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1–7). Physiol Rew. 2018;98(1):505-53.
51. Figueiredo VP, Barbosa MA, de Castro UGM, Zacarias AC, Bezerra FS, de Sá RG, et al. Antioxidant Effects of Oral Ang-(1-7) Restore Insulin Pathway and RAS Components Ameliorating Cardiometabolic Disturbances in Rats. Oxid Med Cell Longev. 2019;2019.
52. Jiang T, Gao L, Guo J, Lu J, Wang Y, Zhang Y. Suppressing inflammation by inhibiting the NF‐κB pathway contributes to the neuroprotective effect of angiotensin‐(1‐7) in rats with permanent cerebral ischaemia. Br J Pharmacol. 2012;167(7):1520-32.
53. Zhang Z, Chen L, Zhong J, Gao P, Oudit GY. ACE2/Ang-(1–7) signaling and vascular remodeling. Sci China Life Sci. 2014;57(8):802-8.
54. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmune. 2020:102433.
55. Patel AB, Verma A. COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: What Is the Evidence? JAMA. 2020.
56. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020.
57. Abazari O, Shafaei Z, Divsalar A, Eslami-Moghadam M, Ghalandari B, Saboury AA, et al. Interaction of the synthesized anticancer compound of the methyl-glycine 1, 10-phenanthroline platinum nitrate with human serum albumin and human hemoglobin proteins by spectroscopy methods and molecular docking. JICS. 2020:1-14.
58. Grady CL, Springer MV, Hongwanishkul D, McIntosh AR, Winocur G. Age-related changes in brain activity across the adult lifespan. J Cogn Neurosci 2006;18(2):227-41.
59. Hoffmann M, Kleine-Weber H, Krüger N, Mueller MA, Drosten C, Pöhlmann S. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells. BioRxiv. 2020.
60. Lambert DW, Yarski M, Warner FJ, Thornhill P, Parkin ET, Smith AI, et al. Tumor necrosis factor-α convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J BiolChem. 2005;280(34):30113-9.
61. Sheahan TP, Sims AC, Leist SR, Schäfer A, Won J, Brown AJ, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. NatCommun . 2020;11(1):1-14.
62. Ben Mkaddem S, BENANI A. Mechanisms underlying potential therapeutic approaches to COVID-19. Front Immunol. 2020;11:1841.
63. Lu H. Drug treatment options for the 2019-new coronavirus (2019-nCoV). Biosci Trends. 2020;14(1):69-71.
64. Wu C, Chen X, Cai Y, Zhou X, Xu S, Huang H, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020.
65. Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R. Features, evaluation and treatment coronavirus (COVID-19). StatPearls [Internet]: StatPearls Publishing; 2020.
66. Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer RA, Stahl M, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell. 2020.
67. Russo V, Di Maio M, Attena E, Silverio A, Scudiero F, Celentani D, et al. Clinical impact of pre-admission antithrombotic therapy in hospitalized patients with COVID-19: a multicenter observational study. Pharmacol Res. 2020;159:104965.
68. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020.
69. Furuhashi M, Moniwa N, Mita T, Fuseya T, Ishimura S, Ohno K, et al. Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker. Am J Hypertens. 2015;28(1):15-21.
70. Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, Brosnihan KB, Ferrario CM. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertens. 2004;43(5):970-6.
71. Meng J, Xiao G, Zhang J, He X, Ou M, Bi J, et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 2020;9(1):757-60.
72. Shafaei Z, Abazari O, Divsalar A, Ghalandari B, Poursoleiman A, Saboury AA, et al. Effect of a Synthesized Amyl-Glycine1, 10-Phenanthroline Platinum Nitrate on Structure and Stability of Human Blood Carrier Protein, Albumin: Spectroscopic and Modeling Approaches. J Fluoresc. 2017;27(5):1829-38.
73. Hsu W-T, Galm BP, Schrank G, Hsu T-C, Lee S-H, Park JY, et al. Effect of Renin-Angiotensin-Aldosterone System Inhibitors on Short-Term Mortality After Sepsis: A Population-Based Cohort Study. Hypertens. 2020;75(2):483-91.
74. Bozkurt B, Kovacs R, Harrington B. Joint HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19. J Card Fail. 2020;26(5):370.
75. Crackower MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002;417(6891):822-8.
76. Hu X, Su J, Zhou Y, Xie X, Peng C, Yuan Z, et al. Repressing CD147 is a novel therapeutic strategy for malignant melanoma. Oncotarget. 2017;8(15):25806.
77. Muramatsu T. Basigin (CD147), a multifunctional transmembrane glycoprotein with various binding partners. J Biochem. 2016;159(5):481-90.
78. Zare Z, Dizaj TN, Lohrasbi A, Sheikhalishahi ZS, Asadi A, Zakeri M, et al. Silibinin inhibits TGF-β-induced MMP-2 and MMP-9 through Smad Signaling pathway in colorectal cancer HT-29 cells. BCCR. 2020;12(2):79-88.
79. Wang K, Chen W, Zhou Y-S, Lian J-Q, Zhang Z, Du P, et al. SARS-CoV-2 invades host cells via a novel route: CD147-spike protein. bioRxiv. 2020.
80. De Wilde AH, Zevenhoven-Dobbe JC, Beugeling C, Chatterji U, De Jong D, Gallay P, et al. Coronaviruses and arteriviruses display striking differences in their cyclophilin A-dependence during replication in cell culture. Virology. 2018;517:148-56.
81. De Wilde AH, Falzarano D, Zevenhoven-Dobbe JC, Beugeling C, Fett C, Martellaro C, et al. Alisporivir inhibits MERS-and SARS-coronavirus replication in cell culture, but not SARS-coronavirus infection in a mouse model. Virus Res. 2017;228:7-13.
82. Yurchenko V, Constant S, Eisenmesser E, Bukrinsky M. Cyclophilin–CD147 interactions: a new target for anti‐inflammatory therapeutics. Clin Exp Immunol. 2010;160(3):305-17.
83. Glowacka I, Bertram S, Müller MA, Allen P, Soilleux E, Pfefferle S, et al. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. J Virol. 2011;85(9):4122-34.
84. Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N. TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection. J Virol. 2019;93(6):e01815-18.
85. Kawase M, Shirato K, van der Hoek L, Taguchi F, Matsuyama S. Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry. J Virol. 2012;86(12):6537-45.
86. Zhou Y, Vedantham P, Lu K, Agudelo J, Carrion Jr R, Nunneley JW, et al. Protease inhibitors targeting coronavirus and filovirus entry.Antivir Res. 2015;116:76-84.
87. Yang H, Xie W, Xue X, Yang K, Ma J, Liang W, et al. Design of wide-spectrum inhibitors targeting coronavirus main proteases. PLoS biol. 2005;3(10).
88. Bertram S, Heurich A, Lavender H, Gierer S, Danisch S, Perin P, et al. Influenza and SARS-coronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts. PloS one. 2012;7(4).
89. Simmons G, Gosalia DN, Rennekamp AJ, Reeves JD, Diamond SL, Bates P. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc Natl Acad Sci. 2005;102(33):11876-81.
90. Zhang H, Baker A. Recombinant human ACE2: acing out angiotensin II in ARDS therapy. Springer; 2017.
91. Diaz JH. Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19. J Travel Med. 2020;10.
92. Tai W, He L, Zhang X, Pu J, Voronin D, Jiang S, et al. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol. 2020:1-8.
93. Wang Z, Yang B, Li Q, Wen L, Zhang R. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China. Clin Infect Dis. 2020.
94. Zhou P, Yang X-L, Wang X-G, Hu B, Zhang L, Zhang W, et al. Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin. BioRxiv. 2020.
95. Venkatesan B, Valente AJ, Prabhu SD, Shanmugam P, Delafontaine P, Chandrasekar B. EMMPRIN activates multiple transcription factors in cardiomyocytes, and induces interleukin-18 expression via Rac1-dependent PI3K/Akt/IKK/NF-κB and MKK7/JNK/AP-1 signaling. J Mol Cell Cardiol. 2010;49(4):655-63.
96. Mercure C, Yogi A, Callera GE, Aranha AB, Bader M, Ferreira AJ, et al. Angiotensin (1-7) blunts hypertensive cardiac remodeling by a direct effect on the heart. Circ Res. 2008;103(11):1319-26.
97. Thakur S, Du J, Hourani S, Ledent C, Li J-M. Inactivation of adenosine A2A receptor attenuates basal and angiotensin II-induced ROS production by Nox2 in endothelial cells.JBiol Chem. 2010;285(51):40104-13.
98. Perrucci GL, Straino S, Corlianò M, Scopece A, Napolitano M, Berk BC, et al. Cyclophilin A modulates bone marrow-derived CD117+ cells and enhances ischemia-induced angiogenesis via the SDF-1/CXCR4 axis.Int J Cardiol . 2016;212:324-35.
99. Zhang R, Pan Y, Fanelli V, Wu S, Luo AA, Islam D, et al. Mechanical stress and the induction of lung fibrosis via the midkine signaling pathway. Am J Respir Crit Care Med. 2015;192(3):315-23.
100. Wösten‐van Asperen RM, Lutter R, Specht PA, Moll GN, van Woensel JB, van der Loos CM, et al. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin‐(1–7) or an angiotensin II receptor antagonist. J Pathol. 2011;225(4):618-27.
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IssueVol 20 No 1 (2021) QRcode
SectionReview Article(s)
Published2021-02-11
Keywords
Angiotensin-converting enzyme 2 COVID-19 SARS-COV-2 Therapeutics

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Musavi H, Abazari O, Safaee M S, Variji A, Koohshekan B, Kalaki-Jouybari F, Barartabar Z, Hakemi P, Mahjoub S. Mechanisms of COVID-19 Entry into the Cell: Potential Therapeutic Approaches Based on Virus Entry Inhibition in COVID-19 Patients with Underlying Diseases. Iran J Allergy Asthma Immunol. 20(1):11-23.