Focus on Receptors for Coronaviruses with Special Reference to Angiotensin- Converting Enzyme 2 as a Potential Drug Target - A Perspective

Author(s): Thea Magrone, Manrico Magrone, Emilio Jirillo*

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders

Volume 20 , Issue 6 , 2020


DOI : 10.2174/1871530320666200427112902

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[1]
Fehr, A.R.; 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]
[2]
Du, L.; He, Y.; Zhou, Y.; Liu, S.; Zheng, B.J.; Jiang, S. The spike protein of SARS-CoV--A target for vaccine and therapeutic development. Nat. Rev. Microbiol., 2009, 7(3), 226-236.
[http://dx.doi.org/10.1038/nrmicro2090] [PMID: 19198616]
[3]
Du, L.; Yang, Y.; Zhou, Y.; Lu, L.; Li, F.; Jiang, S. MERS-CoV spike protein: A key target for antivirals. Expert Opin. Ther. Targets, 2017, 21(2), 131-143.
[http://dx.doi.org/10.1080/14728222.2017.1271415] [PMID: 27936982]
[4]
Kuba, K.; Imai, Y.; Rao, S.; Gao, H.; Guo, F.; Guan, B.; Huan, Y.; Yang, P.; Zhang, Y.; Deng, W.; Bao, L.; Zhang, B.; Liu, G.; Wang, Z.; Chappell, M.; Liu, Y.; Zheng, D.; Leibbrandt, A.; Wada, T.; Slutsky, A.S.; Liu, D.; Qin, C.; Jiang, C.; Penninger, J.M. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat. Med., 2005, 11(8), 875-879.
[http://dx.doi.org/10.1038/nm1267] [PMID: 16007097]
[5]
Guo, Y.; Korteweg, C.; McNutt, M.A.; Gu, J. Pathogenetic mechanisms of severe acute respiratory syndrome. Virus Res., 2008, 133(1), 4-12.
[http://dx.doi.org/10.1016/j.virusres.2007.01.022] [PMID: 17825937]
[6]
Lukassen, S.; Lorenz Chua, R.; Trefzer, T.; Kahn, N.C.; Schneider, M.A.; Muley, T.; Winter, H.; Meister, M.; Veith, C.; Boots, A.W.; Hennig, B.P.; Kreuter, M.; Conrad, C.; Eils, R. SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. EMBO J., 2020.e105114
[http://dx.doi.org/10.15252/embj.20105114] [PMID: 32246845]
[7]
Jeffers, S.A.; Tusell, S.M.; Gillim-Ross, L.; Hemmila, E.M.; Achenbach, J.E.; Babcock, G.J.; Thomas, W.D., Jr; Thackray, L.B.; Young, M.D.; Mason, R.J.; Ambrosino, D.M.; Wentworth, D.E.; Demartini, J.C.; Holmes, K.V. CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus. Proc. Natl. Acad. Sci. USA, 2004, 101(44), 15748-15753.
[http://dx.doi.org/10.1073/pnas.0403812101] [PMID: 15496474]
[8]
Widagdo, W.; Raj, V.S.; Schipper, D.; Kolijn, K.; van Leenders, G.J.L.H.; Bosch, B.J.; Bensaid, A.; Segalés, J.; Baumgärtner, W.; Osterhaus, A.D.M.E.; Koopmans, M.P.; van den Brand, J.M.A.; Haagmans, B.L. Differential Expression of the Middle East Respiratory Syndrome Coronavirus Receptor in the Upper Respiratory Tracts of Humans and Dromedary Camels. J. Virol., 2016, 90(9), 4838-4842.
[http://dx.doi.org/10.1128/JVI.02994-15] [PMID: 26889022]
[9]
Qinfen, Z.; Jinming, C.; Xiaojun, H.; Huanying, Z.; Jicheng, H.; Ling, F.; Kunpeng, L.; Jingqiang, Z. The life cycle of SARS coronavirus in Vero E6 cells. J. Med. Virol., 2004, 73(3), 332-337.
[http://dx.doi.org/10.1002/jmv.20095] [PMID: 15170625]
[10]
Qu, X.X.; Hao, P.; Song, X.J.; Jiang, S.M.; Liu, Y.X.; Wang, P.G.; Rao, X.; Song, H.D.; Wang, S.Y.; Zuo, Y.; Zheng, A.H.; Luo, M.; Wang, H.L.; Deng, F.; Wang, H.Z.; Hu, Z.H.; Ding, M.X.; Zhao, G.P.; Deng, H.K. Identification of two critical amino acid residues of the severe acute respiratory syndrome coronavirus spike protein for its variation in zoonotic tropism transition via a double substitution strategy. J. Biol. Chem., 2005, 280(33), 29588-29595.
[http://dx.doi.org/10.1074/jbc.M500662200] [PMID: 15980414]
[11]
Li, W.; Zhang, C.; Sui, J.; Kuhn, J.H.; Moore, M.J.; Luo, S.; Wong, S.K.; Huang, I.C.; Xu, K.; Vasilieva, N.; Murakami, A.; He, Y.; Marasco, W.A.; Guan, Y.; Choe, H.; Farzan, M. Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. EMBO J., 2005, 24(8), 1634-1643.
[http://dx.doi.org/10.1038/sj.emboj.7600640] [PMID: 15791205]
[12]
Wang, N.; Shi, X.; Jiang, L.; Zhang, S.; Wang, D.; Tong, P.; Guo, D.; Fu, L.; Cui, Y.; Liu, X.; Arledge, K.C.; Chen, Y.H.; Zhang, L.; Wang, X. Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4. Cell Res., 2013, 23(8), 986-993.
[http://dx.doi.org/10.1038/cr.2013.92] [PMID: 23835475]
[13]
Chen, Y.; Rajashankar, K.R.; Yang, Y.; Agnihothram, S.S.; Liu, C.; Lin, Y.L.; Baric, R.S.; Li, F. Crystal structure of the receptor-binding domain from newly emerged Middle East respiratory syndrome coronavirus. J. Virol., 2013, 87(19), 10777-10783.
[http://dx.doi.org/10.1128/JVI.01756-13] [PMID: 23903833]
[14]
Wan, Y.; Shang, J.; Graham, R.; Baric, R.S.; 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-e20.
[http://dx.doi.org/10.1128/JVI.00127-20] [PMID: 31996437]
[15]
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), 562-569.
[http://dx.doi.org/10.1038/s41564-020-0688-y] [PMID: 32094589]
[16]
Zhou, P.; Yang, X.L.; Wang, X.G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.R.; Zhu, Y.; Li, B.; Huang, C.L.; Chen, H.D.; Chen, J.; Luo, Y.; Guo, H.; Jiang, R.D.; Liu, M.Q.; Chen, Y.; Shen, X.R.; Wang, X.; Zheng, X.S.; Zhao, K.; Chen, Q.J.; Deng, F.; Liu, L.L.; Yan, B.; Zhan, F.X.; Wang, Y.Y.; Xiao, G.F.; Shi, Z.L. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 2020, 579(7798), 270-273.
[http://dx.doi.org/10.1038/s41586-020-2012-7] [PMID: 32015507]
[17]
Guzzi, P.H.; Mercatelli, D.; Ceraolo, C.; Giorgi, F.M. Master Regulator Analysis of the SARS-CoV-2/Human Interactome. J. Clin. Med., 2020, 9(4),E982.
[http://dx.doi.org/10.3390/jcm9040982] [PMID: 32244779]
[18]
Imai, Y.; Kuba, K.; Rao, S.; Huan, Y.; Guo, F.; Guan, B.; Yang, P.; Sarao, R.; Wada, T.; Leong-Poi, H.; Crackower, M.A.; Fukamizu, A.; Hui, C.C.; Hein, L.; Uhlig, S.; Slutsky, A.S.; Jiang, C.; Penninger, J.M. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature, 2005, 436(7047), 112-116.
[http://dx.doi.org/10.1038/nature03712] [PMID: 16001071]
[19]
Batlle, D.; Wysocki, J.; Satchell, K. Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy? Clin. Sci. (Lond.), 2020, 134(5), 543-545.
[http://dx.doi.org/10.1042/CS20200163] [PMID: 32167153]
[20]
Spiegel, M.; Pichlmair, A.; Martínez-Sobrido, L.; Cros, J.; García-Sastre, A.; Haller, O.; Weber, F. Inhibition of Beta interferon induction by severe acute respiratory syndrome coronavirus suggests a two-step model for activation of interferon regulatory factor 3. J. Virol., 2005, 79(4), 2079-2086.
[http://dx.doi.org/10.1128/JVI.79.4.2079-2086.2005] [PMID: 15681410]
[21]
Kopecky-Bromberg, S.A.; Martínez-Sobrido, L.; Frieman, M.; Baric, R.A.; Palese, P. Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists. J. Virol., 2007, 81(2), 548-557.
[http://dx.doi.org/10.1128/JVI.01782-06] [PMID: 17108024]
[22]
Lu, X.; Pan, J.; Tao, J.; Guo, D. SARS-CoV nucleocapsid protein antagonizes IFN-β response by targeting initial step of IFN-β induction pathway, and its C-terminal region is critical for the antagonism. Virus Genes, 2011, 42(1), 37-45.
[http://dx.doi.org/10.1007/s11262-010-0544-x] [PMID: 20976535]
[23]
Chen, J.; Lau, Y.F.; Lamirande, E.W.; Paddock, C.D.; Bartlett, J.H.; Zaki, S.R.; Subbarao, K. Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection. J. Virol., 2010, 84(3), 1289-1301.
[http://dx.doi.org/10.1128/JVI.01281-09] [PMID: 19906920]
[24]
Yang, Y.; Xiong, Z.; Zhang, S.; Yan, Y.; Nguyen, J.; Ng, B.; Lu, H.; Brendese, J.; Yang, F.; Wang, H.; Yang, X.F. Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors. Biochem. J., 2005, 392(Pt 1), 135-143.
[http://dx.doi.org/10.1042/BJ20050698] [PMID: 16048439]
[25]
Mubarak, A.; Alturaiki, W.; Hemida, M.G. Middle East Respiratory Syndrome Coronavirus (MERS-CoV): Infection, Immunological Response, and Vaccine Development. J. Immunol. Res., 2019, 2019,6491738.
[http://dx.doi.org/10.1155/2019/6491738] [PMID: 31089478]
[26]
Ng, O.W.; Chia, A.; Tan, A.T.; Jadi, R.S.; Leong, H.N.; Bertoletti, A.; Tan, Y.J. Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection. Vaccine, 2016, 34(17), 2008-2014.
[http://dx.doi.org/10.1016/j.vaccine.2016.02.063] [PMID: 26954467]
[27]
Ababneh, M.; Alrwashdeh, M.; Khalifeh, M. Recombinant adenoviral vaccine encoding the spike 1 subunit of the Middle East Respiratory Syndrome Coronavirus elicits strong humoral and cellular immune responses in mice. Vet. World, 2019, 12(10), 1554-1562.
[http://dx.doi.org/10.14202/vetworld.2019.1554-1562] [PMID: 31849416]
[28]
Chen, Z.; Bao, L.; Chen, C.; Zou, T.; Xue, Y.; Li, F.; Lv, Q.; Gu, S.; Gao, X.; Cui, S.; Wang, J.; Qin, C.; Jin, Q. Human Neutralizing Monoclonal Antibody Inhibition of Middle East Respiratory Syndrome Coronavirus Replication in the Common Marmoset. J. Infect. Dis., 2017, 215(12), 1807-1815.
[http://dx.doi.org/10.1093/infdis/jix209] [PMID: 28472421]
[29]
Niu, P.; Zhao, G.; Deng, Y.; Sun, S.; Wang, W.; Zhou, Y.; Tan, W. A novel human mAb (MERS-GD27) provides prophylactic and postexposure efficacy in MERS-CoV susceptible mice. Sci. China Life Sci., 2018, 61(10), 1280-1282.
[http://dx.doi.org/10.1007/s11427-018-9343-8] [PMID: 30091015]
[30]
Niu, P.; Zhang, S.; Zhou, P.; Huang, B.; Deng, Y.; Qin, K.; Wang, P.; Wang, W.; Wang, X.; Zhou, J.; Zhang, L.; Tan, W. Ultrapotent Human Neutralizing Antibody Repertoires Against Middle East Respiratory Syndrome Coronavirus From a Recovered Patient. J. Infect. Dis., 2018, 218(8), 1249-1260.
[http://dx.doi.org/10.1093/infdis/jiy311] [PMID: 29846635]
[31]
Chen, W.; Xu, Z.; Mu, J.; Yang, L.; Gan, H.; Mu, F.; Fan, B.; He, B.; Huang, S.; You, B.; Yang, Y.; Tang, X.; Qiu, L.; Qiu, Y.; Wen, J.; Fang, J.; Wang, J. Antibody response and viraemia during the course of severe acute respiratory syndrome (SARS)-associated coronavirus infection. J. Med. Microbiol., 2004, 53(Pt 5), 435-438.
[http://dx.doi.org/10.1099/jmm.0.45561-0] [PMID: 15096554]
[32]
Yang, X.; Yu, Y.; Xu, J.; Shu, H.; Xia, J.; Liu, H.; Wu, Y.; Zhang, L.; Yu, Z.; Fang, M.; Yu, T.; Wang, Y.; Pan, S.; Zou, X.; Yuan, S.; Shang, Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir. Med.,, 2020,, S2213-2600(20), 30079- 30075..
[http://dx.doi.org/10.1016/S2213-2600(20)30079-5] [PMID: 32105632]
[33]
Ruan, Q.; Yang, K.; Wang, W.; Jiang, L.; Song, J. Correction to: Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med., 2020.
[http://dx.doi.org/10.1007/s00134-020-06028-z] [PMID: 32253449]
[34]
Conti, P.; Ronconi, G.; Caraffa, A.; Gallenga, C.E.; Ross, R.; Frydas, I.; Kritas, S.K. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J. Biol. Regul. Homeost. Agents , 2020, 34(2) pii: 1,
[http://dx.doi.org/10.23812/CONTI-E] [PMID: 32171193]
[35]
Porcheddu, R.; Serra, C.; Kelvin, D.; Kelvin, N.; Rubino, S. Similarity in Case Fatality Rates (CFR) of COVID-19/SARS-COV-2 in Italy and China. J. Infect. Dev. Ctries., 2020, 14(2), 125-128.
[http://dx.doi.org/10.3855/jidc.12600] [PMID: 32146445]
[36]
Magrone, T.; Magrone, M.; Russo, M.A.; Jirillo, E. Peripheral immunosenescence and central neuroinflammation: A dangerous liaison. A dietary approach. Endocr. Metab. Immune Disord. Drug Targets, 2020.
[http://dx.doi.org/10.2174/1871530320666200406123734] [PMID: 32250234]
[37]
Oudit, G.Y.; Crackower, M.A.; Backx, P.H.; Penninger, J.M. The role of ACE2 in cardiovascular physiology. Trends Cardiovasc. Med., 2003, 13(3), 93-101.
[http://dx.doi.org/10.1016/S1050-1738(02)00233-5] [PMID: 12691672]
[38]
Hunyady, L.; Catt, K.J. Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. Mol. Endocrinol., 2006, 20(5), 953-970.
[http://dx.doi.org/10.1210/me.2004-0536] [PMID: 16141358]
[39]
Carey, R.M. Cardiovascular and renal regulation by the angiotensin type 2 receptor: the AT2 receptor comes of age. Hypertension, 2005, 45(5), 840-844.
[http://dx.doi.org/10.1161/01.HYP.0000159192.93968.8f] [PMID: 15738342]
[40]
Gurwitz, D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev. Res., 2020.
[http://dx.doi.org/10.1002/ddr.21656] [PMID: 32129518]
[41]
Ishiyama, Y.; Gallagher, P.E.; Averill, D.B.; Tallant, E.A.; Brosnihan, K.B.; Ferrario, C.M. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension, 2004, 43(5), 970-976.
[http://dx.doi.org/10.1161/01.HYP.0000124667.34652.1a] [PMID: 15007027]
[42]
Tiao, M.M.; Lin, Y.J.; Yu, H.R.; Sheen, J.M.; Lin, I.C.; Lai, Y.J.; Tain, Y.L.; Huang, L.T.; Tsai, C.C. Resveratrol ameliorates maternal and post-weaning high-fat diet-induced nonalcoholic fatty liver disease via renin-angiotensin system. Lipids Health Dis., 2018, 17(1), 178.
[http://dx.doi.org/10.1186/s12944-018-0824-3] [PMID: 30055626]
[43]
Kim, E.N.; Kim, M.Y.; Lim, J.H.; Kim, Y.; Shin, S.J.; Park, C.W.; Kim, Y.S.; Chang, Y.S.; Yoon, H.E.; Choi, B.S. The protective effect of resveratrol on vascular aging by modulation of the renin-angiotensin system. Atherosclerosis, 2018, 270, 123-131.
[http://dx.doi.org/10.1016/j.atherosclerosis.2018.01.043] [PMID: 29407880]
[44]
Oliveira Andrade, J.M.; Paraíso, A.F.; Garcia, Z.M.; Ferreira, A.V.; Sinisterra, R.D.; Sousa, F.B.; Guimarães, A.L.; de Paula, A.M.; Campagnole-Santos, M.J.; dos Santos, R.A.; Santos, S.H. Cross talk between angiotensin-(1-7)/Mas axis and sirtuins in adipose tissue and metabolism of high-fat feed mice. Peptides, 2014, 55, 158-165.
[http://dx.doi.org/10.1016/j.peptides.2014.03.006] [PMID: 24642355]
[45]
Zordoky, B.N.; Robertson, I.M.; Dyck, J.R. Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases. Biochim. Biophys. Acta, 2015, 1852(6), 1155-1177.
[http://dx.doi.org/10.1016/j.bbadis.2014.10.016] [PMID: 25451966]
[46]
Baur, J.A.; Pearson, K.J.; Price, N.L.; Jamieson, H.A.; Lerin, C.; Kalra, A.; Prabhu, V.V.; Allard, J.S.; Lopez-Lluch, G.; Lewis, K.; Pistell, P.J.; Poosala, S.; Becker, K.G.; Boss, O.; Gwinn, D.; Wang, M.; Ramaswamy, S.; Fishbein, K.W.; Spencer, R.G.; Lakatta, E.G.; Le Couteur, D.; Shaw, R.J.; Navas, P.; Puigserver, P.; Ingram, D.K.; de Cabo, R.; Sinclair, D.A. Resveratrol improves health and survival of mice on a high-calorie diet. Nature, 2006, 444(7117), 337-342.
[http://dx.doi.org/10.1038/nature05354] [PMID: 17086191]
[47]
Miyazaki, R.; Ichiki, T.; Hashimoto, T.; Inanaga, K.; Imayama, I.; Sadoshima, J.; Sunagawa, K. SIRT1, a longevity gene, downregulates angiotensin II type 1 receptor expression in vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol., 2008, 28(7), 1263-1269.
[http://dx.doi.org/10.1161/ATVBAHA.108.166991] [PMID: 18420994]
[48]
Lin, S.C.; Ho, C.T.; Chuo, W.H.; Li, S.; Wang, T.T.; Lin, C.C. Effective inhibition of MERS-CoV infection by resveratrol. BMC Infect. Dis., 2017, 17(1), 144.
[http://dx.doi.org/10.1186/s12879-017-2253-8] [PMID: 28193191]
[49]
Magrone, T.; Magrone, M.; Russo, M.A.; Jirillo, E. Recent Advances on the Anti-Inflammatory and Antioxidant Properties of Red Grape Polyphenols: In vitro and In vivo Studies. Antioxidants, 2020, 9(1),E35.
[http://dx.doi.org/10.3390/antiox9010035] [PMID: 31906123]
[50]
Hanff, T.C.; Harhay, M.O.; Brown, T.S.; Cohen, J.B.; Mohareb, A.M. Is There an Association Between COVID-19 Mortality and the Renin-Angiotensin System-a Call for Epidemiologic Investigations. Clin. Infect. Dis., 2020, ciaa329.,
[http://dx.doi.org/10.1093/cid/ciaa329] [PMID: 32215613]
[51]
Danser, A.H.J.; Epstein, M.; Batlle, D. Renin-Angiotensin System Blockers and the COVID-19 Pandemic: At Present There Is No Evidence to Abandon Renin-Angiotensin System Blockers. Hypertension,, 2020,, 75, 00-00.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15082] [PMID: 32208987]
[52]
Kuster, G.M.; Pfister, O.; Burkard, T.; Zhou, Q.; Twerenbold, R.; Haaf, P.; Widmer, A.F.; Osswald, S. SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? Eur. Heart J., 2020, pii: ehaa235
[http://dx.doi.org/10.1093/eurheartj/ehaa235] [PMID: 32196087]
[53]
Gu, J.; Korteweg, C. Pathology and pathogenesis of severe acute respiratory syndrome. Am. J. Pathol., 2007, 170(4), 1136-1147.
[http://dx.doi.org/10.2353/ajpath.2007.061088] [PMID: 17392154]


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VOLUME: 20
ISSUE: 6
Year: 2020
Published on: 17 July, 2020
Page: [807 - 811]
Pages: 5
DOI: 10.2174/1871530320666200427112902

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