Volume 9, Issue 1 (Vol.9 No.1 Apr 2020)                   rbmb.net 2020, 9(1): 97-105 | Back to browse issues page


XML Print


Pharmacology department, Medical College, Jouf University, KSA. & Pharmacology department, Faculty of Medicine, Beni-Suef University, Egypt.
Abstract:   (4731 Views)
Background: Since its first appearance in December of 2019, regular updates around the world demonstrates that the number of new Corona Virus 2019 (COVID-19) cases are increasing rapidly, indicating that not only does COVID-19 exhibit a rapid spread pattern, but human intervention is necessary for its resolution. Up until today (27-5-2020) and according to the World Health Organization (WHO), the number of confirmed COVID-19 cases has surpassed 4.5 million with more than 307, 500 deaths. Almost all countries have been affected by COVID-19, and resultingly, various drug trials have been conducted, however, a targeted treatment remains to be made accessible to the public. Recently, Angiotensin-Converting Enzyme-2 (ACE2) has gained some attention for its discovery as a potential attachment target of COVID-19.

Methods: We reviewed the most recent evidence regarding ACE2 distribution and action, the binding mechanism of COVID-19 and its correlation to cellular injury, ACE2 polymorphisms and its association to fatal COVID-19 and susceptibility and, finally, current ACE2-based pharmacotherapies against COVID-19.

Results: Blocking the ACE2 receptor-binding domain (RBD) using a specific ligand can prevent COVID-19 from binding, and consequently cellular entry and injury. Comparatively, soluble ACE2, which has a higher affinity to COVID-19, can neutralize COVID-19 without affecting the homeostatic function of naturally occurring ACE2. Lastly, ACE2 mutations and their possible effect on the binding activity of COVID-19 may enable researchers to identify high-risk groups before they become exposed to COVID-19.

Conclusions: ACE2 represents a promising target to attenuate or prevent COVID-19 associated cellular injury.
Keywords: ACE, ACE2, COVID-19.
Full-Text [PDF 211 kb]   (2647 Downloads)    
Type of Article: Review | Subject: Molecular Biology
Received: 2020/05/21 | Accepted: 2020/06/8 | Published: 2020/07/18

References
1. 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. The lancet. 2020;395(10223):497-506. [DOI:10.1016/S0140-6736(20)30183-5]
2. Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000;275(43):33238-43. [DOI:10.1074/jbc.M002615200] [PMID]
3. Hamming I, Timens W, Bulthuis M, Lely A, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004;203(2):631-637. [DOI:10.1002/path.1570] [PMID] [PMCID]
4. Xu H, Zhong L, Deng J, Peng J, Dan H, Zeng X, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. International Journal of Oral Science. 2020;12(1):1-5. [DOI:10.1038/s41368-020-0074-x] [PMID] [PMCID]
5. Jackman HL, Massad MG, Sekosan M, Tan F, Brovkovych V, Marcic BM, et al. Angiotensin 1-9 and 1-7 release in human heart: role of cathepsin A. Hypertension. 2002;39(5):976-81. [DOI:10.1161/01.HYP.0000017283.67962.02] [PMID]
6. Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 2002;277(17):14838-43. [DOI:10.1074/jbc.M200581200] [PMID]
7. Sayed-Tabatabaei F, Oostra B, Isaacs A, Van Duijn C, Witteman J. ACE polymorphisms. Circ Res. 2006;98(9):1123-33. [DOI:10.1161/01.RES.0000223145.74217.e7] [PMID]
8. Turner A. Exploring the structure and function of zinc metallopeptidases: old enzymes and new discoveries. Biochem Soc Trans. 2003;31(Pt 3):723-7. [DOI:10.1042/bst0310723] [PMID]
9. Jaspard E, Wei L, Alhenc-Gelas F. Differences in the properties and enzymatic specificities of the two active sites of angiotensin I-converting enzyme (kininase II). Studies with bradykinin and other natural peptides. J Biol Chem. 1993;268(13):9496-503.
10. Brewster UC, Perazella MA. The renin-angiotensin-aldosterone system and the kidney: effects on kidney disease. The American journal of medicine. 2004;116(4):263-272. [DOI:10.1016/j.amjmed.2003.09.034] [PMID]
11. Aroor A, Zuberek M, Duta C, Meuth A, Sowers JR, Whaley-Connell A, et al. Angiotensin II stimulation of DPP4 activity regulates megalin in the proximal tubules. Int J Mol Sci. 2016;17(5):780. [DOI:10.3390/ijms17050780] [PMID] [PMCID]
12. Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, et al. A novel angiotensin- converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000;87(5):e1-9. [DOI:10.1161/01.RES.87.5.e1] [PMID]
13. Carluccio M, Soccio M, De Caterina R. Aspects of gene polymorphisms in cardiovascular disease: the renin‐angiotensin system. Eur J Clin Invest. 2001;31(6):476-88. [DOI:10.1046/j.1365-2362.2001.00839.x] [PMID]
14. Turner AJ, Tipnis SR, Guy JL, Rice GI, Hooper NM. ACEH/ACE2 is a novel mammalian metallocarboxypeptidase and a homologue of angiotensin-converting enzyme insensitive to ACE inhibitors. Canadian journal of physiology and pharmacology. 2002;80(4):346-53. [DOI:10.1139/y02-021] [PMID]
15. Gu J, Gong E, Zhang B, Zheng J, Gao Z, Zhong Y, et al. Multiple organ infection and the pathogenesis of SARS. J Exp Med. 2005;202(3):415-424. [DOI:10.1084/jem.20050828] [PMID] [PMCID]
16. Raizada MK, Ferreira AJ. ACE2: a new target for cardiovascular disease therapeutics. J Cardiovasc Pharmacol. 2007;50(2):112-9. [DOI:10.1097/FJC.0b013e3180986219] [PMID]
17. Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J. 2004;383(Pt 1):45-51. [DOI:10.1042/BJ20040634] [PMID] [PMCID]
18. Riviere G, Michaud A, Breton C, VanCamp G, Laborie C, Enache M, et al. Angiotensin-converting enzyme 2 (ACE2) and ACE activities display tissue-specific sensitivity to undernutrition-programmed hypertension in the adult rat. Hypertension. 2005;46(5):1169-74. [DOI:10.1161/01.HYP.0000185148.27901.fe] [PMID]
19. Santos RA, e Silva ACS, Maric C, Silva DM, Machado RP, de Buhr I, et al. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proceedings of the National Academy of Sciences. 2003;100(14):8258-63. [DOI:10.1073/pnas.1432869100] [PMID] [PMCID]
20. Kostenis E, Milligan G, Christopoulos A, Sanchez-Ferrer CF, Heringer-Walther S, Sexton PM, et al. G-protein-coupled receptor Mas is a physiological antagonist of the angiotensin II type 1 receptor. Circulation. 2005;111(14):1806-13. [DOI:10.1161/01.CIR.0000160867.23556.7D] [PMID]
21. Sampaio WO, Souza dos Santos RA, Faria-Silva R, da Mata Machado LT, Schiffrin EL, Touyz RM. Angiotensin-(1-7) through receptor Mas mediates endothelial nitric oxide synthase activation via Akt-dependent pathways. Hypertension. 2007;49(1):185-92. [DOI:10.1161/01.HYP.0000251865.35728.2f] [PMID]
22. Pedersen KB, Chhabra KH, Nguyen VK, Xia H, Lazartigues E. The transcription factor HNF1alpha induces expression of angiotensin-converting enzyme 2 (ACE2) in pancreatic islets from evolutionarily conserved promoter motifs. Biochim Biophys Acta. 2013;1829(11):1225-35. [DOI:10.1016/j.bbagrm.2013.09.007] [PMID] [PMCID]
23. Reich HN, Oudit GY, Penninger JM, Scholey JW, Herzenberg AM. Decreased glomerular and tubular expression of ACE2 in patients with type 2 diabetes and kidney disease. Kidney Int. 2008;74(12):1610-6. [DOI:10.1038/ki.2008.497] [PMID]
24. Patel VB, Zhong J-C, Grant MB, Oudit GY. Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure. Circ Res. 2016;118(8):1313-1326. [DOI:10.1161/CIRCRESAHA.116.307708] [PMID] [PMCID]
25. Rutkowska‐Zapała M, Suski M, Szatanek R, Lenart M, Węglarczyk K, Olszanecki R, et al. Human monocyte subsets exhibit divergent angiotensin I‐converting activity. Clinical & Experimental Immunology. 2015;181(1):126-32. [DOI:10.1111/cei.12612] [PMID] [PMCID]
26. Rey-Parra G, Vadivel A, Coltan L, Hall A, Eaton F, Schuster M, et al. Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury. J Mol Med (Berl). 2012;90(6):637-47. [DOI:10.1007/s00109-012-0859-2] [PMID] [PMCID]
27. Qi Y, Zhang J, Cole-Jeffrey CT, Shenoy V, Espejo A, Hanna M, et al. Diminazene aceturate enhances angiotensin-converting enzyme 2 activity and attenuates ischemia-induced cardiac pathophysiology. Hypertension. 2013;62(4):746-52. [DOI:10.1161/HYPERTENSIONAHA.113.01337] [PMID] [PMCID]
28. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J virol. 2020;94(7):e00127-20. [DOI:10.1128/JVI.00127-20] [PMID] [PMCID]
29. Li XC, Zhang J, Zhuo JL. The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res. 2017;125(Pt A):21-38. [DOI:10.1016/j.phrs.2017.06.005] [PMID] [PMCID]
30. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-733. [DOI:10.1056/NEJMoa2001017] [PMID] [PMCID]
31. Simmons G, Zmora P, Gierer S, Heurich A, Pohlmann S. Proteolytic activation of the SARS-coronavirus spike protein: cutting enzymes at the cutting edge of antiviral research. Antiviral Res. 2013;100(3):605-14. [DOI:10.1016/j.antiviral.2013.09.028] [PMID] [PMCID]
32. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh C-L, Abiona O, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020;367(6483):1260-1263. [DOI:10.1126/science.abb2507] [PMID] [PMCID]
33. Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci. 2020;63(3):457-460. [DOI:10.1007/s11427-020-1637-5] [PMID] [PMCID]
34. Li F, Li W, Farzan M, Harrison SC. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science. 2005;309(5742):1864-8. [DOI:10.1126/science.1116480] [PMID]
35. Yang X-h, Deng W, Tong Z, Liu Y-x, Zhang L-f, Zhu H, et al. Mice transgenic for human angiotensin-converting enzyme 2 provide a model for SARS coronavirus infection. Comp Med. 2007;57(5):450-9.
36. Liu CX, Hu Q, Wang Y, Zhang W, Ma ZY, Feng JB, et al. Angiotensin-Converting Enzyme (ACE) 2 Overexpression Ameliorates Glomerular Injury in a Rat Model of Diabetic Nephropathy: A Comparison with ACE Inhibition. Mol Med. 2011;17(1-2):59-69. [DOI:10.2119/molmed.2010.00111] [PMID] [PMCID]
37. Ding Y, He L, Zhang Q, Huang Z, Che X, Hou J, et al. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS‐CoV) in SARS patients: implications for pathogenesis and virus transmission pathways. J Pathol. 2004;203(2):622-630. [DOI:10.1002/path.1560] [PMID] [PMCID]
38. Zhao Y, Zhao Z, Wang Y, Zhou Y, Ma Y, Zuo W. Single-cell RNA expression profiling of ACE2, the putative receptor of Wuhan 2019-nCov. BioRxiv. 2020. [DOI:10.1101/2020.01.26.919985]
39. 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. [DOI:10.1038/nature11228] [PMID] [PMCID]
40. 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):1061-1069. [DOI:10.1001/jama.2020.1585] [PMID] [PMCID]
41. Corman VM, Landt O, Kaiser M, Molenkamp R, Meijer A, Chu DK, et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill. 2020;25(3):2000045. [DOI:10.2807/1560-7917.ES.2020.25.3.2000045] [PMID] [PMCID]
42. 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(4):e21. [DOI:10.1016/S2213-2600(20)30116-8]
43. Cai G. Bulk and single-cell transcriptomics identify tobacco-use disparity in lung gene expression of ACE2, the receptor of 2019-nCov. MedRxiv. 2020. [DOI:10.20944/preprints202002.0051.v2]
44. Cao Y, Li L, Feng Z, Wan S, Huang P, Sun X, et al. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov. 2020;6:11. [DOI:10.1038/s41421-020-0147-1] [PMID] [PMCID]
45. 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. [DOI:10.1038/nature00786] [PMID]
46. Diez-Freire C, Vazquez J, Correa de Adjounian MaF, Ferrari MF, Yuan L, Silver X, et al. ACE2 gene transfer attenuates hypertension-linked pathophysiological changes in the SHR. Physiol Genomics. 2006;27(1):12-9. [DOI:10.1152/physiolgenomics.00312.2005] [PMID]
47. Tikellis C, Pickering R, Tsorotes D, Du X-J, Kiriazis H, Nguyen-Huu T-P, et al. Interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes. Clin Sci (Lond). 2012;123(8):519-29. [DOI:10.1042/CS20110668] [PMID]
48. Velkoska E, Patel SK, Burrell LM. Angiotensin converting enzyme 2 and diminazene: role in cardiovascular and blood pressure regulation. Curr Opin Nephrol Hypertens. 2016;25(5):384-95. [DOI:10.1097/MNH.0000000000000254] [PMID]
49. Luo Y, Liu C, Guan T, Li Y, Lai Y, Li F, et al. Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in south Xinjiang. Hypertens Res. 2019;42(5):681-689. https://doi.org/10.1038/s41440-019-0205-y [DOI:10.1038/s41440-018-0166-6]
50. Chen Y, Liu D, Zhang P, Zhong J, Zhang C, Wu S, et al. Impact of ACE2 gene polymorphism on antihypertensive efficacy of ACE inhibitors. J Hum Hypertens. 2016;30(12):766-771. [DOI:10.1038/jhh.2016.24] [PMID]
51. Fan Xh, Wang Yb, Wang H, Sun K, Zhang W-l, Song Xd, et al. Polymorphisms of angiotensin-converting enzyme (ACE) and ACE2 are not associated with orthostatic blood pressure dysregulation in hypertensive patients. Acta Pharmacol Sin. 2009;30(9):1237-44. [DOI:10.1038/aps.2009.110] [PMID] [PMCID]
52. Niu W, Qi Y, Hou S, Zhou W, Qiu C. Correlation of angiotensin-converting enzyme 2 gene polymorphisms with stage 2 hypertension in Han Chinese. Translational research. 2007;150(6):374-380. [DOI:10.1016/j.trsl.2007.06.002] [PMID]
53. Malard L, Kakinami L, O'Loughlin J, Roy-Gagnon M-H, Labbe A, Pilote L, et al. The association between the angiotensin-converting enzyme-2 gene and blood pressure in a cohort study of adolescents. BMC Med Genet. 2013;14:117. [DOI:10.1186/1471-2350-14-117] [PMID] [PMCID]
54. Chen Q, Tang X, Yu C, Chen D, Tian J, Cao Y, et al. Correlation of angiotensin-converting enzyme 2 gene polymorphism with antihypertensive effects of benazepril. Beijing da xue xue bao Yi xue ban. 2010;42(3):293-298.
55. Patnaik M, Pati P, Swain SN, Mohapatra MK, Dwibedi B, Kar SK, et al. Association of angiotensin-converting enzyme and angiotensin-converting enzyme-2 gene polymorphisms with essential hypertension in the population of Odisha, India. Ann Hum Biol. 2014;41(2):145-52. [DOI:10.3109/03014460.2013.837195] [PMID]
56. Pinheiro DS, Santos RS, Jardim PCV, Silva EG, Reis AA, Pedrino GR, et al. The combination of ACE I/D and ACE2 G8790A polymorphisms revels susceptibility to hypertension: A genetic association study in Brazilian patients. PloS one. 2019;14(8): e0221248. [DOI:10.1371/journal.pone.0221248] [PMID] [PMCID]
57. Liu C, Li Y, Guan T, Lai Y, Shen Y, Zeyaweiding A, et al. ACE2 polymorphisms associated with cardiovascular risk in Uygurs with type 2 diabetes mellitus. Cardiovascular diabetology. 2018;17:127. [DOI:10.1186/s12933-018-0771-3] [PMID] [PMCID]
58. Meng N, Zhang Y, Ma J, Li H, Zhou F, Qu Y. Association of polymorphisms of angiotensin I converting enzyme 2 with retinopathy in type 2 diabetes mellitus among Chinese individuals. Eye (Lond). 2015;29(2):266-71. [DOI:10.1038/eye.2014.254] [PMID] [PMCID]
59. Fan Z, Wu G, Yue M, Ye J, Chen Y, Xu B, et al. Hypertension and hypertensive left ventricular hypertrophy are associated with ACE2 genetic polymorphism. Life sci. 2019;225:39-45. [DOI:10.1016/j.lfs.2019.03.059] [PMID]
60. Wysocki J, Ye M, Soler MJ, Gurley SB, Xiao HD, Bernstein KE, et al. ACE and ACE2 activity in diabetic mice. Diabetes. 2006;55(7):2132-9. [DOI:10.2337/db06-0033] [PMID]
61. Rabelo LA, Todiras M, Nunes-Souza V, Qadri F, Szijarto IA, Gollasch M, et al. Genetic deletion of ACE2 induces vascular dysfunction in C57BL/6 mice: role of nitric oxide imbalance and oxidative stress. PloS one. 2016;11(4):e0150255. [DOI:10.1371/journal.pone.0150255] [PMID] [PMCID]
62. Ioana M, Ferwerda B, Farjadian S, Ioana L, Ghaderi A, Oosting M, et al. High variability of TLR4 gene in different ethnic groups in Iran. Innate immun. 2012;18(3):492-502. [DOI:10.1177/1753425911423043] [PMID]
63. Raj VS, Mou H, Smits SL, Dekkers DH, Müller MA, Dijkman R, et al. Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC. Nature. 2013;495(7440):251-4. [DOI:10.1038/nature12005] [PMID] [PMCID]
64. Nargis T, Kumar K, Ghosh AR, Sharma A, Rudra D, Sen D, et al. KLK5 induces shedding of DPP4 from circulatory Th17 cells in type 2 diabetes. Molecular metabolism. 2017;6(11):1529-1539. [DOI:10.1016/j.molmet.2017.09.004] [PMID] [PMCID]
65. Kleine-Weber H, Schroeder S, Krüger N, Prokscha A, Naim HY, Müller MA, et al. Polymorphisms in dipeptidyl peptidase 4 reduce host cell entry of Middle East respiratory syndrome coronavirus. Emerg Microbes Infect. 2020;9(1):155-168. [DOI:10.1080/22221751.2020.1713705] [PMID] [PMCID]
66. Asselta R, Paraboschi EM, Mantovani A, Duga S. ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy. Aging (Albany NY). 2020;12(11):10087-10098. [DOI:10.18632/aging.103415] [PMID] [PMCID]
67. Calcagnile M, Forgez P, Iannelli A, Bucci C, Alifano M, Alifano P. ACE2 polymorphisms and individual susceptibility to SARS-CoV-2 infection: insights from an in silico study. bioRxiv. 2020. [DOI:10.1101/2020.04.23.057042] [PMID]
68. Yu L, Yuan K, Phuong HTA, Park BM, Kim SH. Angiotensin-(1-5), an active mediator of renin-angiotensin system, stimulates ANP secretion via Mas receptor. Peptides. 2016;86:33-41. [DOI:10.1016/j.peptides.2016.09.009] [PMID]
69. Zhang H, Baker A. Recombinant human ACE2: acing out angiotensin II in ARDS therapy. Crit Care. 2017;21(1):305. [DOI:10.1186/s13054-017-1882-z] [PMID] [PMCID]
70. Khan A, Benthin C, Zeno B, Albertson TE, Boyd J, Christie JD, et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care. 2017;21(1):234. [DOI:10.1186/s13054-017-1823-x] [PMID] [PMCID]
71. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science. 2020;367(6485):1444-144 [DOI:10.1126/science.abb2762] [PMID] [PMCID]

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.