Targeting Angiotensin-converting Enzyme 2 (ACE2) for the Discovery of
Anticoronaviral Drugs

Narayana   Subbiah Hari Narayana   Moorthy; Chandrabose      Karthikeyan; Elangovan      Manivannan

Abstract

Coronaviruses are a leading cause of emerging life-threatening diseases, as evidenced by the ongoing coronavirus disease pandemic (COVID-19). According to complete genome sequence analysis reports, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes COVID-19, has a sequence identity highly similar to the earlier severe acute respiratory syndrome coronavirus (SARSCoV). The SARS-CoV-2 has the same mode of transmission, replication, and pathogenicity as SARSCoV. The SARS-CoV-2 spike protein's receptor-binding domain (RBD) binds to host angiotensinconverting enzyme-2 (ACE2). The ACE2 is overexpressed in various cells, most prominently epithelial cells of the lung (surface of type 1 and 2 pneumocytes), intestine, liver, kidney, and nervous system. As a result, these organs are more vulnerable to SARS-CoV-2 infection.

Furthermore, renin-angiotensin system (RAS) blockers, which are used to treat cardiovascular diseases, intensify ACE2 expression, leading to an increase in the risk of COVID-19. ACE2 hydrolyzes angiotensin- II (carboxypeptidase) to heptapeptide angiotensin (1-7) and releases a C-terminal amino acid. By blocking the interaction of spike protein with ACE2, the SARS-CoV-2 entry into the host cell and internalization can be avoided. The pathogenicity of SARS-CoV-2 could be reduced by preventing the RBD from attaching to ACE2-expressing cells. Therefore, inhibition or down-regulation of ACE2 in host cells represents a therapeutic strategy to fight against COVID-19. However, ACE2 plays an essential role in the physiological pathway, protecting against hypertension, heart failure, myocardial infarction, acute respiratory lung disease, and diabetes. Given the importance of ACE's homeostatic role, targeting of ACE2 should be realized with caution. Above all, focusing on the SARS-CoV-2 spike protein and the ACE2 gene in the host cell is an excellent way to avoid viral mutation and resistance. The current review summarises the sequence analysis, structure of coronavirus, ACE2, spike protein-ACE2 complex, essential structural characteristics of the spike protein RBD, and ACE2 targeted approaches for anti-coronaviral drug design and development.

Keywords: Coronavirus, SARS-CoV, SARS-CoV-2, ACE2, spike protein, COVID-19, glycoproteins.

Graphical Abstract

[1]
Schaffer K, La Rosa AM, Whimbey E. Chapter 162 - Respiratory viruses. Infectious Diseases.  3rd Edition. Cohen J, Opal SM, Powderly WH. Amsterdam: Elsevier Science B. 2010; 2: pp. 1598-608.

[2]
Gorbalenya AE, Baker SC, Baric RS, et al. The species severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol  2020; 5(4): 536-44.
 [http://dx.doi.org/10.1038/s41564-020-0695-z] [PMID:  32123347]

[3]
Chen J, Jiang Q, Xia X, et al. Individual variation of the SARS-CoV2 receptor ACE2 gene expression and regulation. Aging Cell  2020; 19(17): e13168.

[4]
Huentelman MJ, Zubcevic J, et al. Structure-based discovery of a novel angiotensin-converting enzyme 2 inhibitor. Hypertension  2004; 44(6): 903-6.
 [http://dx.doi.org/10.1161/01.HYP.0000146120.29648.36] [PMID:  15492138]

[5]
Schoeman D, Fielding BC. Coronavirus envelope protein: Current knowledge. Virol J  2019; 16(1): 69.
 [http://dx.doi.org/10.1186/s12985-019-1182-0] [PMID:  31133031]

[6]
de Groot RJ, Baker SC, Baric R, et al. Family Coronaviridae. Virus taxonomy. King AMQ, Adams MJ, Carstens EB, Lefkowitz EJ Ninth report of the international committee on taxonomy of viruses.  Amsterdam: Elsevier Academic Press 2012; II: pp. 806-28.

[7]
Xu H, Zhong L, Deng J, et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci  2020; 12(1): 8.
 [http://dx.doi.org/10.1038/s41368-020-0074-x] [PMID:  32094336]

[8]
Graham RL, Baric RS. Recombination, reservoirs, and the modular spike: Mechanisms of coronavirus cross-species transmission. J Virol  2010; 84(7): 3134-46.
 [http://dx.doi.org/10.1128/JVI.01394-09] [PMID:  19906932]

[9]
Li F. Receptor recognition and cross-species infections of SARS coronavirus. Antiviral Res  2013; 100(1): 246-54.
 [http://dx.doi.org/10.1016/j.antiviral.2013.08.014] [PMID:  23994189]

[10]
Li W, Wong SK, Li F, et al. Animal origins of the severe acute respiratory syndrome coronavirus: Insight from ACE2-S-protein interac-tions. J Virol  2006; 80(9): 4211-9.
 [http://dx.doi.org/10.1128/JVI.80.9.4211-4219.2006] [PMID:  16611880]

[11]
Li F. Structure, function, and evolution of coronavirus spike proteins. Annu Rev Virol  2016; 3(1): 237-61.
 [http://dx.doi.org/10.1146/annurev-virology-110615-042301] [PMID:  27578435]

[12]
Tai W, He L, Zhang X, et al. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: Implication for develop-ment of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol  2020; 17(6): 613-20.
 [http://dx.doi.org/10.1038/s41423-020-0400-4] [PMID:  32203189]

[13]
Cao Z, Liu L, Du L, et al. Potent and persistent antibody responses against the receptor-binding domain of SARS-CoV spike protein in recovered patients. Virol J  2010; 7: 299.
 [http://dx.doi.org/10.1186/1743-422X-7-299]

[14]
Tao K, Tzou PL, Nouhin J, et al. The biological and clinical significance of emerging SARS-CoV-2 variants. Nat Rev Genet  2021; 22(12): 757-73.
 [http://dx.doi.org/10.1038/s41576-021-00408-x] [PMID:  34535792]

[15]
Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and recep-tor binding. Lancet  2020; 395(10224): 565-74.
 [http://dx.doi.org/10.1016/S0140-6736(20)30251-8] [PMID:  32007145]

[16]
Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature  2020; 579(7798): 270-3.
 [http://dx.doi.org/10.1038/s41586-020-2012-7] [PMID:  32015507]

[17]
Xu X, Chen P, Wang J, 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): 457-60.
 [http://dx.doi.org/10.1007/s11427-020-1637-5] [PMID:  32009228]

[18]
Hofmann H, Pyrc K, van der Hoek L, Geier M, Berkhout B. PAhlmann S. Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry. Proc Natl Acad Sci USA  2005; 102(22): 7988-93.
 [http://dx.doi.org/10.1073/pnas.0409465102] [PMID:  15897467]

[19]
Vankadari N, Wilce JA. Emerging Wuhan (COVID-19) coronavirus: Glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26. Emerg Microbes Infect  2020; 9(1): 601-4.
 [http://dx.doi.org/10.1080/22221751.2020.1739565] [PMID:  32178593]

[20]
Song W, Gui M, Wang X, Xiang Y. Cryo-EM structure of the SARS coronavirus spike glycoprotein in complex with its host cell receptor ACE2. PLoS Pathog  2018; 14(8): e1007236.
 [http://dx.doi.org/10.1371/journal.ppat.1007236] [PMID:  30102747]

[21]
Millet JK, Kien F, Cheung C-Y, et al. Ezrin interacts with the SARS coronavirus Spike protein and restrains infection at the entry stage. PLoS One  2012; 7(11): e49566.
 [http://dx.doi.org/10.1371/journal.pone.0049566] [PMID:  23185364]

[22]
Liu Z, Xiao X, Wei X, et al. Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential inter-mediate hosts of SARS-CoV-2. J Med Virol  2020; 92(6): 595-601.
 [http://dx.doi.org/10.1002/jmv.25726] [PMID:  32100877]

[23]
Kannan S, Shaik Syed Ali P, Sheeza A, Hemalatha K. COVID-19 (novel coronavirus 2019) - recent trends. Eur Rev Med Pharmacol Sci  2020; 24(4): 2006-11.
 [PMID:  32141569]

[24]
Fehr AR, Perlman S. Coronaviruses: An overview of their replication and pathogenesis. Methods Mol Biol  2015; 1282: 1-23.
 [http://dx.doi.org/10.1007/978-1-4939-2438-7_1] [PMID:  25720466]

[25]
Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glyco-protein. Cell  2020; 180: 1-12.

[26]
de Haan CA, Kuo L, Masters PS, Vennema H, Rottier PJM. Coronavirus particle assembly: Primary structure requirements of the mem-brane protein. J Virol  1998; 72(8): 6838-50.
 [http://dx.doi.org/10.1128/JVI.72.8.6838-6850.1998] [PMID:  9658133]

[27]
Holmes KV, Doller EW, Sturman LS. Tunicamycin resistant glycosylation of coronavirus glycoprotein: Demonstration of a novel type of viral glycoprotein. Virol  1981; 115: 334-44.

[28]
Tok TT, Tatar G. Structures and functions of coronavirus proteins: Molecular modeling of viral nucleoprotein. Int J Virol Infect Dis  2017; 2(1): 001-7.

[29]
Raamsman MJB, Locker JK, de Hooge A, et al. Characterization of the coronavirus mouse hepatitis virus strain A59 small membrane protein E. J Virol  2000; 74(5): 2333-42.
 [http://dx.doi.org/10.1128/JVI.74.5.2333-2342.2000] [PMID:  10666264]

[30]
Hwa K-Y, Lin WM, Hou Y-I, Yeh TM. Peptide mimicry between SARS coronavirus spike protein and human proteins reacts with SARS patient serum. J Biomed Biotechnol  2008; 2008: 326464.
 [http://dx.doi.org/10.1155/2008/326464]

[31]
Li F. Receptor recognition mechanisms of coronaviruses: A decade of structural studies. J Virol  2015; 89(4): 1954-64.
 [http://dx.doi.org/10.1128/JVI.02615-14] [PMID:  25428871]

[32]
Shang J, Wan Y, Liu C, et al. Structure of mouse coronavirus spike protein complexed with receptor reveals mechanism for viral entry. PLoS Pathog  2020; 16(3): e1008392.
 [http://dx.doi.org/10.1371/journal.ppat.1008392] [PMID:  32150576]

[33]
Yuan Y, Cao D, Zhang Y, et al. Cryo-EM structures of MERS-CoV and SARS-CoV spike glycoproteins reveal the dynamic receptor bind-ing domains. Nat Commun  2017; 8: 15092.
 [http://dx.doi.org/10.1038/ncomms15092] [PMID:  28393837]

[34]
Gui M, Song W, Zhou H, et al. Cryo-electron microscopy structures of the SARS-CoV spike glycoprotein reveal a prerequisite conforma-tional state for receptor binding. Cell Res  2017; 27(1): 119-29.
 [http://dx.doi.org/10.1038/cr.2016.152] [PMID:  28008928]

[35]
Wong SK, Li W, Moore MJ, Choe H, Farzan M. A 193-amino acid fragment of the SARS coronavirus S protein efficiently binds angioten-sin-converting enzyme 2. J Biol Chem  2004; 279(5): 3197-201.
 [http://dx.doi.org/10.1074/jbc.C300520200] [PMID:  14670965]

[36]
Shi Z, Wang LF. Evolution of SARS coronavirus and the relevance of modern molecular epidemiology.  Genetics Evol Infect Dis 2011; pp. 711-28.

[37]
Triposkiadis F, Xanthopoulos A, Giamouzis G, et al. ACE2, the counter-regulatory renin-angiotensin system axis and COVID-19 severity. J Clin Med  2021; 10(17): 3885.
 [http://dx.doi.org/10.3390/jcm10173885] [PMID:  34501332]

[38]
Glowacka I, Bertram S, Herzog P, et al. Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63. J Virol  2010; 84(2): 1198-205.
 [http://dx.doi.org/10.1128/JVI.01248-09] [PMID:  19864379]

[39]
Peiris JSM, Guan Y, Yuen KY. Severe acute respiratory syndrome. Nat Med  2004; 10(12) (Suppl.): S88-97.
 [http://dx.doi.org/10.1038/nm1143] [PMID:  15577937]

[40]
Goulter AB, Goddard MJ, Allen JC, Clark KL. ACE2 gene expression is up-regulated in the human failing heart. BMC Med  2004; 2: 19.
 [http://dx.doi.org/10.1186/1741-7015-2-19] [PMID:  15151696]

[41]
Turner AJ. Chapter 25 - ACE2 cell biology, regulation, and physiological functions The Protective Arm of the Renin-Angiotensin System.  RAS 2015; pp. 185-9.
 [http://dx.doi.org/10.1016/B978-0-12-801364-9.00025-0]

[42]
Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature  2003; 426(6965): 450-4.
 [http://dx.doi.org/10.1038/nature02145] [PMID:  14647384]

[43]
Oudit GY, Imai Y, Kuba K, Scholey JW, Penninger JM. The role of ACE2 in pulmonary diseases-relevance for the nephrologist. Nephrol Dial Transplant  2009; 24(5): 1362-5.
 [http://dx.doi.org/10.1093/ndt/gfp065] [PMID:  19228756]

[44]
Tikellis C, Thomas MC. Angiotensin-converting enzyme 2 (ACE2) is a crucial modulator of the renin-angiotensin system in health and disease. Int J Pept  2012; 2012: 256294.
 [PMID:  22536270]

[45]
Lambert DW, Clarke NE, Hooper NM, Turner AJ. Calmodulin interacts with angiotensin-converting enzyme-2 (ACE2) and inhibits shed-ding of its ectodomain. FEBS Lett  2008; 582(2): 385-90.
 [http://dx.doi.org/10.1016/j.febslet.2007.11.085] [PMID:  18070603]

[46]
Kiely DG, Cargill RI, Wheeldon NM, Coutie WJ, Lipworth BJ. Haemodynamic and endocrine effects of type 1 angiotensin II receptor blockade in patients with hypoxaemic cor pulmonale. Cardiovasc Res  1997; 33(1): 201-8.
 [http://dx.doi.org/10.1016/S0008-6363(96)00180-0] [PMID:  9059545]

[47]
Ingelfinger JR. ACE2: A new target for prevention of diabetic nephropathy? J Am Soc Nephrol  2006; 17(11): 2957-9.
 [http://dx.doi.org/10.1681/ASN.2006090986] [PMID:  17021263]

[48]
Singh R, Singh AK, Leehey DJ. A novel mechanism for angiotensin II formation in streptozotocin-diabetic rat glomeruli. Am J Physiol Renal Physiol  2005; 288(6): F1183-90.
 [http://dx.doi.org/10.1152/ajprenal.00159.2003] [PMID:  15701818]

[49]
Shukla AK, Banerjee M. Angiotensin-converting-enzyme 2 and renin-angiotensin system inhibitors in COVID-19: An update. High Blood Press Cardiovasc Prev  2021; 28(2): 129-39.
 [http://dx.doi.org/10.1007/s40292-021-00439-9] [PMID:  33635533]

[50]
Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res  2020; 81(5): 537-40.
 [http://dx.doi.org/10.1002/ddr.21656] [PMID:  32129518]

[51]
Towler P, Staker B, Prasad SG, et al. ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catal-ysis. J Biol Chem  2004; 279(17): 17996-8007.
 [http://dx.doi.org/10.1074/jbc.M311191200] [PMID:  14754895]

[52]
Rushworth CA, Guy JL, Turner AJ. Residues affecting the chloride regulation and substrate selectivity of the angiotensin-converting en-zymes (ACE and ACE2) identified by site-directed mutagenesis. FEBS J  2008; 275(23): 6033-42.
 [http://dx.doi.org/10.1111/j.1742-4658.2008.06733.x] [PMID:  19021774]

[53]
Chamsi-Pasha MAR, Shao Z, Tang WHW. Angiotensin-converting enzyme 2 as a therapeutic target for heart failure. Curr Heart Fail Rep  2014; 11(1): 58-63.
 [http://dx.doi.org/10.1007/s11897-013-0178-0] [PMID:  24293035]

[54]
Verdecchia P, Cavallini C, Spanevello A, Angeli F. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med  2020; 76: 14-20.
 [http://dx.doi.org/10.1016/j.ejim.2020.04.037] [PMID:  32336612]

[55]
HernAndez Prada JA, Ferreira AJ, Katovich MJ, et al. Structure-based identification of small-molecule angiotensin-converting enzyme 2 activa-tors as novel antihypertensive agents. Hypertension  2008; 51(5): 1312-7.
 [http://dx.doi.org/10.1161/HYPERTENSIONAHA.107.108944] [PMID:  18391097]

[56]
Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: Molecular mechanisms and potential therapeutic target. Intensive Care Med  2020; 46(4): 586-90.
 [http://dx.doi.org/10.1007/s00134-020-05985-9] [PMID:  32125455]

[57]
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.
 [http://dx.doi.org/10.1126/science.1116480] [PMID:  16166518]

[58]
Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS. J Virol  2020; 94(7): e00127-20.
 [http://dx.doi.org/10.1128/JVI.00127-20] [PMID:  31996437]

[59]
Li W, Choe H, Farzan M. Insights from the association of SARS-CoV S-protein with its receptor, ACE2. Adv Exp Med Biol  2006; 581: 209-18.
 [http://dx.doi.org/10.1007/978-0-387-33012-9_36] [PMID:  17037532]

[60]
Chatterjee B, Thakur SS. ACE2 as a potential therapeutic target for pandemic COVID-19. RSC Advances  2020; 10: 39808-13.
 [http://dx.doi.org/10.1039/D0RA08228G]

[61]
He Y, Li J, Li W, Lustigman S, Farzan M, Jiang S. Cross-neutralization of human and palm civet severe acute respiratory syndrome coro-naviruses by antibodies targeting the receptor-binding domain of spike protein. J Immunol  2006; 176(10): 6085-92.
 [http://dx.doi.org/10.4049/jimmunol.176.10.6085] [PMID:  16670317]

[62]
Tian X, Li C, Huang A, et al. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerg Microbes Infect  2020; 9(1): 382-5.
 [http://dx.doi.org/10.1080/22221751.2020.1729069] [PMID:  32065055]

[63]
Ferrara F, Vitiello A. The renin-angiotensin system and specifically angiotensin-converting enzyme 2 as a potential therapeutic target in SARS-CoV-2 infections. Naunyn Schmiedebergs Arch Pharmacol  2021; 394(7): 1589-93.
 [http://dx.doi.org/10.1007/s00210-021-02108-z] [PMID:  34151392]

[64]
Wu CY, Jan JT, Ma SH, et al. Small molecules targeting severe acute respiratory syndrome human coronavirus. Proc Natl Acad Sci USA  2004; 101(27): 10012-7.
 [http://dx.doi.org/10.1073/pnas.0403596101] [PMID:  15226499]

[65]
Wu CJ, Jan JT, Chen CM, et al. Inhibition of severe acute respiratory syndrome coronavirus replication by niclosamide. Antimicrob Agents Chemother  2004; 48(7): 2693-6.
 [http://dx.doi.org/10.1128/AAC.48.7.2693-2696.2004] [PMID:  15215127]

[66]
Chen F, Chan KH, Jiang Y, et al. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol  2004; 31(1): 69-75.
 [http://dx.doi.org/10.1016/j.jcv.2004.03.003] [PMID:  15288617]

[67]
Yi L, Li Z, Yuan K, et al. Small molecules blocking the entry of severe acute respiratory syndrome coronavirus into host cells. J Virol  2004; 78(20): 11334-9.
 [http://dx.doi.org/10.1128/JVI.78.20.11334-11339.2004] [PMID:  15452254]

[68]
Ye M, Wysocki J, William J, Soler MJ, Cokic I, Batlle D. Glomerular localization and expression of angiotensin-converting enzyme 2 and angiotensin-converting enzyme: Implications for albuminuria in diabetes. J Am Soc Nephrol  2006; 17(11): 3067-75.
 [http://dx.doi.org/10.1681/ASN.2006050423] [PMID:  17021266]

[69]
Boncristiani HF, Criado MF, Arruda E. Respiratory viruses. Encyclopedia of Microbiology.  Third Edition 2009; pp. 500-18.
 [http://dx.doi.org/10.1016/B978-012373944-5.00314-X]

[70]
Xue X, Yu H, Yang H, et al. Structures of two coronavirus main proteases: Implications for substrate binding and antiviral drug design. J Virol  2008; 82(5): 2515-27.
 [http://dx.doi.org/10.1128/JVI.02114-07] [PMID:  18094151]

[71]
Haga S, Nagata N, Okamura T, et al. TACE antagonists blocking ACE2 shedding caused by the spike protein of SARS-CoV are candidate antiviral compounds. Antiviral Res  2010; 85(3): 551-5.
 [http://dx.doi.org/10.1016/j.antiviral.2009.12.001] [PMID:  19995578]

[72]
Beigel JH, Nam HH, Adams PL, et al. Advances in respiratory virus therapeutics - A meeting report from the 6th isirv Antiviral Group conference. Antiviral Res  2019; 167: 45-67.
 [http://dx.doi.org/10.1016/j.antiviral.2019.04.006] [PMID:  30974127]

[73]
Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov  2020; 19(3): 149-50.
 [http://dx.doi.org/10.1038/d41573-020-00016-0] [PMID:  32127666]

[74]
Indari O, Jakhmola S, Manivannan E, Jha HC. An update on antiviral therapy against SARS-CoV-2: How far have we come? Front Pharmacol  2021; 12: 632677.
 [http://dx.doi.org/10.3389/fphar.2021.632677] [PMID:  33762954]

[75]
Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneu-monia in clinical studies. Biosci Trends  2020; 14(1): 72-3.
 [http://dx.doi.org/10.5582/bst.2020.01047] [PMID:  32074550]

[76]
Manivannan E, Karthikeyan C, Moorthy NSHN, Chaturvedi SC. The rise and fall of chloroquine/hydroxychloroquine as compassionate therapy of COVID-19. Front Pharmacol  2021; 12: 584940.
 [http://dx.doi.org/10.3389/fphar.2021.584940] [PMID:  34025393]

[77]
Luo H, Tang QL, Shang YX, et al. Can Chinese medicine be used for prevention of Corona virus disease 2019 (COVID-19)? A review of historical classics, research evidence and current prevention programs. Chin J Integr Med  2020; 26(4): 243-50.
 [http://dx.doi.org/10.1007/s11655-020-3192-6] [PMID:  32065348]

[78]
Sandeep S, McGregor K. Energetics based modeling of hydroxychloroquine and azithromycin binding to the SARS-CoV-2 spike (S)protein - ACE2 complex 2020. 
 [http://dx.doi.org/10.26434/chemrxiv.1201579]

[79]
Rabi FA, Al Zoubi MS, Kasasbeh GA, Salameh DM, Al-Nasser AD. SARS-CoV-2 and coronavirus disease 2019: What we know so far. Pathogens  2020; 9: 231.
 [http://dx.doi.org/10.3390/pathogens9030231]

[80]
Bethesda (MD): National Library of Medicine (US). 2000 Feb 29. Search results of 9 Studies found for: Recruiting, Not yet recruiting, Active, not recruiting, Completed, Enrolling by invitation, Suspended, Terminated, Withdrawn, Unknown status Studies | Interventional Studies | "Coronavirus Infections" and "Chloroquine OR Hydroxychloroquine" Available from: https://www.clinicaltrials.gov/ct2/results?cond= (accessed on March 21, 2020).

[81]
Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res  2020; 30(3): 269-71.

[82]
Jin DY, Zheng BJ. Roles of spike protein in the pathogenesis of SARS coronavirus. Hong Kong Med J  2009; 15 (Suppl. 2): 37-40.
 [PMID:  19258633]

[83]
Du L, He Y, Zhou Y, Liu S, Zheng BJ, Jiang S. The spike protein of SARS-CoV-a target for vaccine and therapeutic development. Nat Rev Microbiol  2009; 7(3): 226-36.
 [http://dx.doi.org/10.1038/nrmicro2090] [PMID:  19198616]

[84]
Chu CM, Cheng VC, Hung IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: Initial virological and clinical findings. Thorax  2004; 59(3): 252-6.
 [http://dx.doi.org/10.1136/thorax.2003.012658] [PMID:  14985565]

[85]
NIH (National Institute of Allergy and Infectious Diseases). NIH Clinical Trial of Remdesivir to Treat COVID-19 Begins  Available from:
          https://www.niaid.nih.gov/news-events/nih-clinical-trial-remdesivirtreat-covid-19-begins(Accessed on 27 February 2020). 

[86]
Gilead Sciences Initiates Two Phase 3 Studies of Investigational Antiviral Remdesivir for the Treatment of COVID-19. Available from: https://www.gilead.com/news-and-press/press-room/press-releases/2020/2/ (Accessed on 27 February 2020).

[87]
Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov  2020; 6: 14.
 [PMID:  32194980]

[88]
Adedeji AO, Severson W, Jonsson C, Singh K, Weiss SR, Sarafianos SG. Novel inhibitors of severe acute respiratory syndrome corona-virus entry that act by three distinct mechanisms. J Virol  2013; 87(14): 8017-28.
 [http://dx.doi.org/10.1128/JVI.00998-13] [PMID:  23678171]

[89]
Amanat F, Nguyen THO, Chromikova V, et al. A serological assay to detect SARS-CoV-2 seroconversion in humans. Nat Med  2020; 26(7): 1033-6.
 [http://dx.doi.org/10.1101/2020.03.17.20037713] [PMID:  32398876]

[90]
Guillon P, Clément M, Sébille V, et al. Inhibition of the interaction between the SARS-CoV spike protein and its cellular receptor by anti-histo-blood group antibodies. Glycobiology  2008; 18(12): 1085-93.
 [http://dx.doi.org/10.1093/glycob/cwn093] [PMID:  18818423]

[91]
Shanmugaraj B, Siriwattananon K, Wangkanont K, Phoolcharoen W. Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19). Asian Pac J Allergy Immunol  2020; 38(1): 10-8.
 [PMID:  32134278]

[92]
Luan J, Lu Y, Jin X, Zhang L. Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2 infection. Biochem Biophys Res Commun  2020; 526(1): 165-9.
 [http://dx.doi.org/10.1016/j.bbrc.2020.03.047] [PMID:  32201080]

[93]
Wang Q, Zhang Y, Wu L, et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell  2020; 181(4): 894-904.e9.
 [http://dx.doi.org/10.1016/j.cell.2020.03.045] [PMID:  32275855]

[94]
Wang Y, Liu M, Gao J. Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions. Proc Natl Acad Sci USA  2020; 117(25): 13967-74.
 [http://dx.doi.org/10.1073/pnas.2008209117] [PMID:  32503918]

Cite As

Coronaviruses

Targeting Angiotensin-converting Enzyme 2 (ACE2) for the Discovery of Anticoronaviral Drugs

Abstract

Graphical Abstract