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The role of proteases in the invasion of SARS-CoV-2 virus into human host cells
Abstract
The new coronavirus, which originally broke out in Wuhan, China, in December 2019, increase quickly around the world, causing a pandemic all over the world. The virus uses its spike protein to enter the human host cells. Protein S binds to the angiotensin-converting enzyme II (ACE2) receptor and enters the host cell. For the more successful binding, several proteases facilitate and optimize this binding, the most important of which are transmembrane protease serine 2 (TMPRSS2), furin, and cathepsin L proteases. After binding of protein S to the ACE2 receptor, cleavage of protein S is required for membrane fusion by protein S, which causes viral entry into host cells. This proteolytic activity may be cathepsin L-dependent and occurs with changes in pH in cell endosomes, or it may occur through serine proteases activity at the surface of the host cell membrane or within vesicles. Finally, the cell becomes infected with the virus. Several studies have tried to reduce the rate of viral infection by using inhibitors of these proteases.
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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):727-33.
Coronavirus disease (COVID-19) Weekly Epidemiological Update and Weekly Operational Update. Retrieved February, 2021 Available at: https://wwwwhoint/emergencies/diseases/novel-coronavirus-2019/situation-reports.
Türsen Ü, Türsen B, Lotti T. Historical corona name in dermatology. Dermatol Ther. 2020; 33(5):e13449.
Zhou P, Yang XL, Wang XG, 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.
Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020; 395(10224):565-74.
Li W, Shi Z, Yu M, Ren W, Smith C, Epstein JH, et al. Bats are natural reservoirs of SARS-like coronaviruses. Science. 2005; 310(5748):676-9.
Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020; 395(10223):514-23.
Coleman CM, Frieman MB. Coronaviruses: important emerging human pathogens. J Virol. 2014; 88(10):5209-12.
Masters PS. The molecular biology of coronaviruses. Adv Virus Res. 2006; 66:193-292.
Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science. 2020; 367(6485):1444-8.
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.
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..
Patel VB, Zhong JC, 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):1313-26.
McCollum LT, Gallagher PE, Ann Tallant E. Angiotensin-(1-7) attenuates angiotensin II-induced cardiac remodeling associated with upregulation of dual-specificity phosphatase 1. Am J Physiol Heart Circ Physiol. 2012; 302(3):H801-10.
Zhang Q, Cong M, Wang N, Li X, Zhang H, Zhang K, et al. Association of angiotensin-converting enzyme 2 gene polymorphism and enzymatic activity with essential hypertension in different gender: A case-control study. Medicine (Baltimore). 2018; 97(42):e12917.
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. Cardiovasc Diabetol. 2018; 17(1):127.
Lukassen S, Chua RL, Trefzer T, Kahn NC, Schneider MA, Muley T, et al. SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. Embo j. 2020; 39(10):e105114.
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020; 181(2):271-80.e8.
Paoloni-Giacobino A, Chen H, Peitsch MC, Rossier C, Antonarakis SE. Cloning of the TMPRSS2 gene, which encodes a novel serine protease with transmembrane, LDLRA, and SRCR domains and maps to 21q22.3. Genomics. 1997; 44(3):309-20.
Jacquinet E, Rao NV, Rao GV, Zhengming W, Albertine KH, Hoidal JR. Cloning and characterization of the cDNA and gene for human epitheliasin. Eur J Biochem. 2001; 268(9):2687-99.
Lucas JM, Heinlein C, Kim T, Hernandez SA, Malik MS, True LD, et al. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer Discov. 2014; 4(11):1310-25.
Lin B, Ferguson C, White JT, Wang S, Vessella R, True LD, et al. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res. 1999; 59(17):4180-4.
Dalpiaz PL, Lamas AZ, Caliman IF, Ribeiro RF, Jr., Abreu GR, Moyses MR, et al. Sex Hormones Promote Opposite Effects on ACE and ACE2 Activity, Hypertrophy and Cardiac Contractility in Spontaneously Hypertensive Rats. PLoS One. 2015; 10(5):e0127515.
Shi Y, Yu X, Zhao H, Wang H, Zhao R, Sheng J. Host susceptibility to severe COVID-19 and establishment of a host risk score: findings of 487 cases outside Wuhan. Crit Care. 2020; 24(1):108.
Gu J, Han B, Wang J. COVID-19: Gastrointestinal Manifestations and Potential Fecal-Oral Transmission. Gastroenterology. 2020; 158(6):1518-9.
Zang R, Gomez Castro MF, McCune BT, Zeng Q, Rothlauf PW, Sonnek NM, et al. TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci Immunol. 2020; 5(47):eabc3582.
Meyer D, Sielaff F, Hammami M, Böttcher-Friebertshäuser E, Garten W, Steinmetzer T. Identification of the first synthetic inhibitors of the type II transmembrane serine protease TMPRSS2 suitable for inhibition of influenza virus activation. Biochem J. 2013; 452(2):331-43.
Zhang X, Zhou Y, Yu X, Huang Q, Fang W, Li J, et al. Differential Roles of Cysteinyl Cathepsins in TGF-β Signaling and Tissue Fibrosis. iScience. 2019; 19:607-22.
Chu VC, McElroy LJ, Chu V, Bauman BE, Whittaker GR. The avian coronavirus infectious bronchitis virus undergoes direct low-pH-dependent fusion activation during entry into host cells. J Virol. 2006; 80(7):3180-8.
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.
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.
Zhou Y, Vedantham P, Lu K, Agudelo J, Carrion R, Jr., Nunneley JW, et al. Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Res. 2015; 116:76-84.
Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun. 2020; 11(1):1620.
Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pöhlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol. 2014; 88(2):1293-307.
Adedeji AO, Severson W, Jonsson C, Singh K, Weiss SR, Sarafianos SG. Novel inhibitors of severe acute respiratory syndrome coronavirus entry that act by three distinct mechanisms. J Virol. 2013; 87(14):8017-28.
Gierer S, Bertram S, Kaup F, Wrensch F, Heurich A, Krämer-Kühl A, et al. The spike protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing antibodies. J Virol. 2013; 87(10):5502-11.
Qian Z, Dominguez SR, Holmes KV. Role of the spike glycoprotein of human Middle East respiratory syndrome coronavirus (MERS-CoV) in virus entry and syncytia formation. PLoS One. 2013; 8(10):e76469.
Shirato K, Kawase M, Matsuyama S. Middle East respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2. J Virol. 2013; 87(23):12552-61.
Fujishima A, Imai Y, Nomura T, Fujisawa Y, Yamamoto Y, Sugawara T. The crystal structure of human cathepsin L complexed with E-64. FEBS Lett. 1997; 407(1):47-50.
Turk V, Stoka V, Vasiljeva O, Renko M, Sun T, Turk B, et al. Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochim Biophys Acta. 2012; 1824(1):68-88.
Lankelma JM, Voorend DM, Barwari T, Koetsveld J, Van der Spek AH, De Porto AP, et al. Cathepsin L, target in cancer treatment? Life Sci. 2010; 86(7-8):225-33.
Lee HS, Lee KJ. Cathepsin B inhibitory peptides derived from beta-casein. Peptides. 2000; 21(6):807-9.
Zhang J, Ma X, Yu F, Liu J, Zou F, Pan T, et al. Teicoplanin potently blocks the cell entry of 2019-nCoV. bioRxiv. 2020:2020.02.05.935387.
Wang H, Yang P, Liu K, Guo F, Zhang Y, Zhang G, et al. SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway. Cell Res. 2008; 18(2):290-301.
Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020; 30(3):269-71.
Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005; 2:69.
Tönnesmann E, Kandolf R, Lewalter T. Chloroquine cardiomyopathy - a review of the literature. Immunopharmacol Immunotoxicol. 2013; 35(3):434-42.
Al-Bari MAA. Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacol Res Perspect. 2017; 5(1):e00293.
Shi Y, Wang Y, Shao C, Huang J, Gan J, Huang X, et al. COVID-19 infection: the perspectives on immune responses. Cell Death Differ. 2020; 27(5):1451-4.
Beers C, Burich A, Kleijmeer MJ, Griffith JM, Wong P, Rudensky AY. Cathepsin S controls MHC class II-mediated antigen presentation by epithelial cells in vivo. J Immunol. 2005; 174(3):1205-12.
Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade. Antiviral Res. 2020; 176:104742.
Millet JK, Whittaker GR. Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein. Proc Natl Acad Sci U S A. 2014; 111(42):15214-9.
Shang J, Wan Y, Luo C, Ye G, Geng Q, Auerbach A, et al. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci U S A. 2020; 117(21):11727-34.
Poon, L.L. (2008) Emerging nidovirus infections. In: Perlman, S., Gallagher, T., and Snijder, E.J. Ed. Nidoviruses. ASM Press, Washington, DC, pp. 409–418.
Wrobel AG, Benton DJ, Xu P, Roustan C, Martin SR, Rosenthal PB, et al. SARS-CoV-2 and bat RaTG13 spike glycoprotein structures inform on virus evolution and furin-cleavage effects. Nat Struct Mol Biol. 2020; 27(8):763-7.
Seidah NG, Day R, Marcinkiewicz M, Chrétien M. Precursor convertases: an evolutionary ancient, cell-specific, combinatorial mechanism yielding diverse bioactive peptides and proteins. Ann N Y Acad Sci. 1998; 839:9-24.
Nakayama K. Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins. Biochem J. 1997; 327 ( Pt 3)(Pt 3):625-35.
Solovyeva NI, Gureeva TA, Timoshenko OS, Moskvitina TA, Kugaevskaya EV. [Furin as proprotein convertase and its role in normaland pathological biological processes]. Biomed Khim. 2016; 62(6):609-21.
Ozden S, Lucas-Hourani M, Ceccaldi PE, Basak A, Valentine M, Benjannet S, et al. Inhibition of Chikungunya virus infection in cultured human muscle cells by furin inhibitors: impairment of the maturation of the E2 surface glycoprotein. J Biol Chem. 2008; 283(32):21899-908.
Shiryaev SA, Remacle AG, Ratnikov BI, Nelson NA, Savinov AY, Wei G, et al. Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens. J Biol Chem. 2007; 282(29):20847-53.
Bestle D, Heindl MR, Limburg H, Van Lam van T, Pilgram O, Moulton H, et al. TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells. Life Sci Alliance. 2020; 3(9):e202000786.
Cheng YW, Chao TL, Li CL, Chiu MF, Kao HC, Wang SH, et al. Furin Inhibitors Block SARS-CoV-2 Spike Protein Cleavage to Suppress Virus Production and Cytopathic Effects. Cell Rep. 2020; 33(2):108254.
DOI: https://doi.org/10.52547/JCBioR.2.1.8
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