Inhibition of Influenza A virus propagation by benzoselenoxanthenes stabilizing TMPRSS2 Gene G-quadruplex and hence down-regulating TMPRSS2 expression.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
06 05 2020
06 05 2020
Historique:
received:
09
08
2018
accepted:
09
04
2020
entrez:
8
5
2020
pubmed:
8
5
2020
medline:
14
5
2020
Statut:
epublish
Résumé
Proteolytic cleavage of influenza A virus (IAV) hemagglutinin by host proteases is crucial for virus infectivity and spread. The transmembrane serine protease TMPRSS2 was previously identified as the essential protease that can cleave hemagglutinin of many subtypes of influenza virus and spike protein of coronavirus. Herein, we found that a guanine rich tract, capable of forming intramolecular G-quadruplex in the presence of potassium ions, in the promoter region of human TMPRSS2 gene was quite important for gene transcriptional activity, hence affecting its function. Furthermore, 7 new synthesized benzoselenoxanthene analogues were found to enable stabilizing such G-quadruplex. More importantly, compounds can down-regulate TMPRSS2 gene expression, especially endogenous TMPRSS2 protein levels, and consequently suppress influenza A virus propagation in vitro. Our results provide a new strategy for anti-influenza A virus infection by small molecules targeting the TMPRSS2 gene G-quadruplex and thus inhibiting TMPRSS2 expression, which is valuable for developing small molecule drugs against influenza A virus and also may be a potential candidate as anti- SARS-CoV-2 (Severe Acute Respiratory Syndrome CoV 2) lead molecules.
Identifiants
pubmed: 32376987
doi: 10.1038/s41598-020-64368-8
pii: 10.1038/s41598-020-64368-8
pmc: PMC7203196
doi:
Substances chimiques
Organoselenium Compounds
0
Serine Endopeptidases
EC 3.4.21.-
TMPRSS2 protein, human
EC 3.4.21.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7635Subventions
Organisme : National Natural Science Foundation of China (National Science Foundation of China)
ID : 21877101
Pays : International
Références
WHO. Influenza https://www.who.int/news-room/fact-sheets/detail/influenza-(seasonal) (6 November 2018).
De Clercq, E. Antiviral agents active against influenza A viruses. Nat. Rev. Drug. Discov. 5, 1015–1025 (2006).
doi: 10.1038/nrd2175
Nguyen, J. T. et al. Triple Combination of Amantadine, Ribavirin, and Oseltamivir Is Highly Active and Synergistic against Drug Resistant Influenza Virus Strains In Vitro. PLoS One 5, e9332 (2010).
doi: 10.1371/journal.pone.0009332
Hu, Y. W. et al. Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. Lancet 381, 2273–2279 (2013).
doi: 10.1016/S0140-6736(13)61125-3
Shen, L. W., Mao, H. J., Wu, Y. L., Tanaka, Y. & Zhang, W. TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections. Biochimie 142, 1–10 (2017).
doi: 10.1016/j.biochi.2017.07.016
Sakai, K. et al. The host protease TMPRSS2 plays a major role in in vivo replication of emerging H7N9 and seasonal influenza viruses. J. Virol. 88, 5608–5616 (2014).
doi: 10.1128/JVI.03677-13
Tarnow, C. et al. TMPRSS2 Is a Host Factor That Is Essential for Pneumotropism and Pathogenicity of H7N9 Influenza A Virus in Mice. J. Virol. 88, 4744–4751 (2014).
doi: 10.1128/JVI.03799-13
Cheng, Z. et al. Identification of TMPRSS2 as a Susceptibility Gene for Severe 2009 Pandemic A(H1N1) Influenza and A(H7N9) Influenza. J. Infect. Dis. 212, 1214–1221 (2015).
doi: 10.1093/infdis/jiv246
Kim, T. S., Heinlein, C., Hackman, R. C. & Nelson, P. S. Phenotypic analysis of mice lacking the Tmprss2-encoded protease. Mol. Cell Biol. 26, 965–975 (2006).
doi: 10.1128/MCB.26.3.965-975.2006
Hoffmann, M. et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 181, 1–10 (2020).
doi: 10.1016/j.cell.2020.02.052
Seenisamy, J. et al. The dynamic character of the G-quadruplex element in the c-MYC promoter and modification by TMPyP4. J. Am. Chem. Soc. 126, 8702–8709 (2004).
doi: 10.1021/ja040022b
Balasubramanian, S. & Neidle, S. G-quadruplex nucleic acids as therapeutic targets. Curr. Opin. Chem. Biol. 13, 345–353 (2009).
doi: 10.1016/j.cbpa.2009.04.637
Biffi, G., Tannahill, D., McCafferty, J. & Balasubramanian, S. Quantitative visualization of DNA G-quadruplex structures in human cells. Nat. Chem. 5, 182–186 (2013).
doi: 10.1038/nchem.1548
Risitano, A. & Fox, K. R. Stability of intramolecular DNA quadruplexes: Comparison with DNA duplexes. Biochemistry-Us 42, 6507–6513 (2003).
doi: 10.1021/bi026997v
Nambiar, M. et al. Formation of a G-quadruplex at the BCL2 major breakpoint region of the t(14;18) translocation in follicular lymphoma. Nucleic Acids Res. 39, 936–948 (2011).
doi: 10.1093/nar/gkq824
Zheng, K. W., Chen, Z., Hao, Y. H. & Tan, Z. Molecular crowding creates an essential environment for the formation of stable G-quadruplexes in long double-stranded DNA. Nucleic Acids Res. 38, 327–338 (2010).
doi: 10.1093/nar/gkp898
Mergny, J. L., Phan, A. T. & Lacroix, L. Following G-quartet formation by UV-spectroscopy. FEBS Lett. 435, 74–78 (1998).
doi: 10.1016/S0014-5793(98)01043-6
Zhang, W. et al. Formation and stabilization of the telomeric antiparallel G-quadruplex and inhibition of telomerase by novel benzothioxanthene derivatives with anti-tumor activity. Sci. Rep-Uk 5, 13693 (2015).
doi: 10.1038/srep13693
Feng, E. G. et al. Recent Advances in Neuraminidase Inhibitor Development as Anti-influenza Drugs. Chem. Med. Chem 7, 1527–1536 (2012).
doi: 10.1002/cmdc.201200155
Glowacka, I. 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. 85, 4122–4134 (2011).
doi: 10.1128/JVI.02232-10
Shirato, K., Kawase, M. & Matsuyama, S. Middle East Respiratory Syndrome Coronavirus Infection Mediated by the Transmembrane Serine Protease TMPRSS2. J. Virol. 87, 12552–12561 (2013).
doi: 10.1128/JVI.01890-13
Bertram, S. et al. TMPRSS2 Activates the Human Coronavirus 229E for Cathepsin-Independent Host Cell Entry and Is Expressed in Viral Target Cells in the Respiratory Epithelium. J. Virol. 87, 6150–6160 (2013).
doi: 10.1128/JVI.03372-12
Gierer, S. 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. 87, 5502–5511 (2013).
doi: 10.1128/JVI.00128-13
Esumi, M. et al. Transmembrane serine protease TMPRSS2 activates hepatitis C virus infection. Hepatology 61, 437–446 (2015).
doi: 10.1002/hep.27426
Zhirnov, O. P., Klenk, N. D. & Wright, P. F. Aprotinin and similar protease inhibitors as drugs against influenza. Antivir. Res. 92, 27–36 (2011).
doi: 10.1016/j.antiviral.2011.07.014
Yamaya, M. et al. The serine protease inhibitor camostat inhibits influenza virus replication and cytokine production in primary cultures of human tracheal epithelial cells. Pulm. Pharmacol. Ther. 33, 66–74 (2015).
doi: 10.1016/j.pupt.2015.07.001
Mangano, D. T., Tudor, I. C., Dietzel, C., Is, M. S. P. & Fdn, I. R. E. The risk associated with aprotinin in cardiac surgery. N. Engl. J. Med. 354, 353–365 (2006).
doi: 10.1056/NEJMoa051379
Onyshchenko, M. I. et al. Stabilization of G-quadruplex in the BCL2 promoter region in double-stranded DNA by invading short PNAs. Nucleic Acids Res. 37, 7570–7580 (2009).
doi: 10.1093/nar/gkp840
Dexheimer, T. S., Sun, D. & Hurley, L. H. Deconvoluting the structural and drug-recognition complexity of the G-quadruplex-forming region upstream of the bcl-2 P1 promoter. J. Am. Chem. Soc. 128, 5404–5415 (2006).
doi: 10.1021/ja0563861
Seenisamy, J. et al. Design and synthesis of an expanded porphyrin that has selectivity for the c-MYC G-quadruplex structure. J. Am. Chem. Soc. 127, 2944–2959 (2005).
doi: 10.1021/ja0444482
Zmora, P. et al. Non-human primate orthologues of TMPRSS2 cleave and activate the influenza virus hemagglutinin. PLoS one 12, e0176597 (2017).
doi: 10.1371/journal.pone.0176597
Sun, Y. et al. Therapeutic effect of apocynin through antioxidant activity and suppression of apoptosis and inflammation after spinal cord injury. Exp. therapeutic Med. 13, 952–960 (2017).
doi: 10.3892/etm.2017.4090
Li, C. X. et al. ‘Obligate’ anaerobic Salmonella strain YB1 suppresses liver tumor growth and metastasis in nude mice. Oncol. Lett. 13, 177–183 (2017).
doi: 10.3892/ol.2016.5453
Baer, A. & Kehn-Hall, K. Viral concentration determination through plaque assays: using traditional and novel overlay systems. J. Vis. Exp. 93, e52065 (2014).