1887

Abstract

The possible resistance of influenza virus against existing antiviral drugs calls for new therapeutic concepts. One appealing strategy is to inhibit virus entry, in particular at the stage of internalization. This requires a better understanding of virus–host interactions during the entry process, including the role of receptor tyrosine kinases (RTKs). To search for cellular targets, we evaluated a panel of 276 protein kinase inhibitors in a multicycle antiviral assay in Madin-Darby canine kidney cells. The RTK inhibitor Ki8751 displayed robust anti-influenza A and B virus activity and was selected for mechanistic investigations. Ki8751 efficiently disrupted the endocytic process of influenza virus in different cell lines carrying platelet-derived growth factor receptor β (PDGFRβ), an RTK that is known to act at GM3 ganglioside-positive lipid rafts. The more efficient virus entry in CHO-K1 cells compared to the wild-type ancestor (CHO-wt) cells indicated a positive effect of GM3, which is abundant in CHO-K1 but not in CHO-wt cells. Entering virus localized to GM3-positive lipid rafts and the PDGFRβ-containing endosomal compartment. PDGFRβ/GM3-dependent virus internalization involved PDGFRβ phosphorylation, which was potently inhibited by Ki8751, and desialylation of activated PDGFRβ by the viral neuraminidase. Virus uptake coincided with strong activation of the Raf/MEK/Erk cascade, but not of PI3K/Akt or phospholipase C-γ. We conclude that influenza virus efficiently hijacks the GM3-enhanced PDGFRβ signalling pathway for cell penetration, providing an opportunity for host cell-targeting antiviral intervention.

  • This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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2019-02-14
2024-03-29
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References

  1. World Health Organization Influenza (seasonal) - Fact sheet No. 211; 2018 Available from: http://www.who.int/mediacentre/factsheets/fs211/en/
  2. Treanor JJ. Clinical practice. Influenza vaccination. N Engl J Med 2016; 375:1261–1268 [View Article][PubMed]
    [Google Scholar]
  3. Nguyen-van-Tam JS, Venkatesan S, Muthuri SG, Myles PR. Neuraminidase inhibitors: who, when, where?. Clin Microbiol Infect 2015; 21:222–225 [View Article][PubMed]
    [Google Scholar]
  4. Moscona A. Global transmission of oseltamivir-resistant influenza. N Engl J Med 2009; 360:953–956 [View Article][PubMed]
    [Google Scholar]
  5. Naesens L, Stevaert A, Vanderlinden E. Antiviral therapies on the horizon for influenza. Curr Opin Pharmacol 2016; 30:106–115 [View Article][PubMed]
    [Google Scholar]
  6. World Health Organization Research needs for the Battle against Respiratory Viruses (BRaVe) - meeting report 2012; 2012 Available from: http://www.who.int/influenza/patient_care/clinical/BRaVE_meeting_report_november2012.pdf
  7. Tripathi S, Pohl MO, Zhou Y, Rodriguez-Frandsen A, Wang G et al. Meta- and orthogonal integration of influenza "omics" data defines a role for UBR4 in virus budding. Cell Host Microbe 2015; 18:723–735 [View Article][PubMed]
    [Google Scholar]
  8. Vanderlinden E, Naesens L. Emerging antiviral strategies to interfere with influenza virus entry. Med Res Rev 2014; 34:301–339 [View Article][PubMed]
    [Google Scholar]
  9. Fujioka Y, Nishide S, Ose T, Suzuki T, Kato I et al. A sialylated voltage-dependent Ca2+ channel binds hemagglutinin and mediates influenza A virus entry into mammalian cells. Cell Host Microbe 2018; 23:809–818 [View Article][PubMed]
    [Google Scholar]
  10. Edinger TO, Pohl MO, Stertz S. Entry of influenza A virus: host factors and antiviral targets. J Gen Virol 2014; 95:263–277 [View Article][PubMed]
    [Google Scholar]
  11. Byrd-Leotis L, Cummings RD, Steinhauer DA. The interplay between the host receptor and influenza virus hemagglutinin and neuraminidase. Int J Mol Sci 2017; 18:1541 [View Article][PubMed]
    [Google Scholar]
  12. Mercer J, Schelhaas M, Helenius A. Virus entry by endocytosis. Annu Rev Biochem 2010; 79:803–833 [View Article][PubMed]
    [Google Scholar]
  13. Zhang Y, Whittaker GR. Influenza entry pathways in polarized MDCK cells. Biochem Biophys Res Commun 2014; 450:234–239 [View Article][PubMed]
    [Google Scholar]
  14. Nunes-Correia I, Eulálio A, Nir S, Pedroso de Lima MC. Caveolae as an additional route for influenza virus endocytosis in MDCK cells. Cell Mol Biol Lett 2004; 9:47–60[PubMed]
    [Google Scholar]
  15. Sieczkarski SB, Whittaker GR. Influenza virus can enter and infect cells in the absence of clathrin-mediated endocytosis. J Virol 2002; 76:10455–10464 [View Article][PubMed]
    [Google Scholar]
  16. de Vries E, Tscherne DM, Wienholts MJ, Cobos-Jiménez V, Scholte F et al. Dissection of the influenza A virus endocytic routes reveals macropinocytosis as an alternative entry pathway. PLoS Pathog 2011; 7:e1001329 [View Article][PubMed]
    [Google Scholar]
  17. König R, Stertz S, Zhou Y, Inoue A, Hoffmann HH et al. Human host factors required for influenza virus replication. Nature 2010; 463:813–817 [View Article][PubMed]
    [Google Scholar]
  18. Eierhoff T, Hrincius ER, Rescher U, Ludwig S, Ehrhardt C. The epidermal growth factor receptor (EGFR) promotes uptake of influenza A viruses (IAV) into host cells. PLoS Pathog 2010; 6:e1001099 [View Article][PubMed]
    [Google Scholar]
  19. Casaletto JB, McClatchey AI. Spatial regulation of receptor tyrosine kinases in development and cancer. Nat Rev Cancer 2012; 12:387–400 [View Article][PubMed]
    [Google Scholar]
  20. Lee IT, Yang CM. Inflammatory signalings involved in airway and pulmonary diseases. Mediators Inflamm 2013; 2013:1–12 [View Article][PubMed]
    [Google Scholar]
  21. Cahill KN, Katz HR, Cui J, Lai J, Kazani S et al. KIT inhibition by imatinib in patients with severe refractory asthma. N Engl J Med 2017; 376:1911–1920 [View Article][PubMed]
    [Google Scholar]
  22. Miljan EA, Bremer EG. Regulation of growth factor receptors by gangliosides. Sci STKE 2002; 2002:re15 [View Article][PubMed]
    [Google Scholar]
  23. Julien S, Bobowski M, Steenackers A, Le Bourhis X, Delannoy P. How do gangliosides regulate RTKs signaling?. Cells 2013; 2:751–767 [View Article][PubMed]
    [Google Scholar]
  24. Matrosovich M, Suzuki T, Hirabayashi Y, Garten W, Webster RG et al. Gangliosides are not essential for influenza virus infection. Glycoconj J 2006; 23:107–113 [View Article][PubMed]
    [Google Scholar]
  25. Desbat B, Lancelot E, Krell T, Nicolaï MC, Vogel F et al. Effect of the β-propiolactone treatment on the adsorption and fusion of influenza A/Brisbane/59/2007 and A/New Caledonia/20/1999 virus H1N1 on a dimyristoylphosphatidylcholine/ganglioside GM3 mixed phospholipids monolayer at the air-water interface. Langmuir 2011; 27:13675–13683 [View Article][PubMed]
    [Google Scholar]
  26. Suzuki Y, Matsunaga M, Nagao Y, Taki T, Hirabayashi Y et al. Ganglioside GM1b as an influenza virus receptor. Vaccine 1985; 3:201–203 [View Article][PubMed]
    [Google Scholar]
  27. Suzuki Y. Gangliosides as influenza virus receptors. Variation of influenza viruses and their recognition of the receptor sialo-sugar chains. Prog Lipid Res 1994; 33:429–457 [View Article][PubMed]
    [Google Scholar]
  28. Kubo K, Shimizu T, Ohyama S, Murooka H, Iwai A et al. Novel potent orally active selective VEGFR-2 tyrosine kinase inhibitors: synthesis, structure-activity relationships, and antitumor activities of N-phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas. J Med Chem 2005; 48:1359–1366 [View Article][PubMed]
    [Google Scholar]
  29. Kimura K, Mori S, Tomita K, Ohno K, Takahashi K et al. Antiviral activity of NMSO3 against respiratory syncytial virus infection in vitro and in vivo. Antiviral Res 2000; 47:41–51 [View Article][PubMed]
    [Google Scholar]
  30. Matrosovich M, Matrosovich T, Carr J, Roberts NA, Klenk HD. Overexpression of the alpha-2,6-sialyltransferase in MDCK cells increases influenza virus sensitivity to neuraminidase inhibitors. J Virol 2003; 77:8418–8425 [View Article][PubMed]
    [Google Scholar]
  31. Ronca R, Giacomini A, di Salle E, Coltrini D, Pagano K et al. Long-pentraxin 3 derivative as a small-molecule FGF trap for cancer therapy. Cancer Cell 2015; 28:225–239 [View Article][PubMed]
    [Google Scholar]
  32. Stevaert A, Dallocchio R, Dessì A, Pala N, Rogolino D et al. Mutational analysis of the binding pockets of the diketo acid inhibitor L-742,001 in the influenza virus PA endonuclease. J Virol 2013; 87:10524–10538 [View Article][PubMed]
    [Google Scholar]
  33. Hoffmann E, Neumann G, Kawaoka Y, Hobom G, Webster RG. A DNA transfection system for generation of influenza A virus from eight plasmids. Proc Natl Acad Sci USA 2000; 97:6108–6113 [View Article][PubMed]
    [Google Scholar]
  34. Vanderlinden E, Vanstreels E, Boons E, Ter Veer W, Huckriede A et al. Intracytoplasmic trapping of influenza virus by a lipophilic derivative of aglycoristocetin. J Virol 2012; 86:9416–9431 [View Article][PubMed]
    [Google Scholar]
  35. Naesens L, Vanderlinden E, Roth E, Jeko J, Andrei G et al. Anti-influenza virus activity and structure-activity relationship of aglycoristocetin derivatives with cyclobutenedione carrying hydrophobic chains. Antiviral Res 2009; 82:89–94 [View Article][PubMed]
    [Google Scholar]
  36. Stevaert A, Nurra S, Pala N, Carcelli M, Rogolino D et al. An integrated biological approach to guide the development of metal-chelating inhibitors of influenza virus PA endonuclease. Mol Pharmacol 2015; 87:323–337 [View Article][PubMed]
    [Google Scholar]
  37. Vanderlinden E, Göktas F, Cesur Z, Froeyen M, Reed ML et al. Novel inhibitors of influenza virus fusion: structure-activity relationship and interaction with the viral hemagglutinin. J Virol 2010; 84:4277–4288 [View Article][PubMed]
    [Google Scholar]
  38. Reed LJ, Muench H. A simple method of estimating fifty per cent endpoints. Am J Epidemiol 1938; 27:493–497 [View Article]
    [Google Scholar]
  39. Kamentsky L, Jones TR, Fraser A, Bray MA, Logan DJ et al. Improved structure, function and compatibility for CellProfiler: modular high-throughput image analysis software. Bioinformatics 2011; 27:1179–1180 [View Article][PubMed]
    [Google Scholar]
  40. Matsuda T, Cepko CL. Electroporation and RNA interference in the rodent retina in vivo and in vitro. Proc Natl Acad Sci USA 2004; 101:16–22 [View Article][PubMed]
    [Google Scholar]
  41. Ulm JW, Perron M, Sodroski J, C Mulligan R. Complex determinants within the Moloney murine leukemia virus capsid modulate susceptibility of the virus to Fv1 and Ref1-mediated restriction. Virology 2007; 363:245–255 [View Article][PubMed]
    [Google Scholar]
  42. Jordan M, Schallhorn A, Wurm FM. Transfecting mammalian cells: optimization of critical parameters affecting calcium-phosphate precipitate formation. Nucleic Acids Res 1996; 24:596–601 [View Article][PubMed]
    [Google Scholar]
  43. de Winter JCF. Using the Student's t-test with extremely small sample sizes. Pract Assess, Res Eval 2013; 18:1–12
    [Google Scholar]
  44. Denisova OV, Söderholm S, Virtanen S, von Schantz C, Bychkov D et al. Akt inhibitor MK2206 prevents influenza pH1N1 virus infection in vitro. Antimicrob Agents Chemother 2014; 58:3689–3696 [View Article][PubMed]
    [Google Scholar]
  45. Hale BG, Knebel A, Botting CH, Galloway CS, Precious BL et al. CDK/ERK-mediated phosphorylation of the human influenza A virus NS1 protein at threonine-215. Virology 2009; 383:6–11 [View Article][PubMed]
    [Google Scholar]
  46. Söderholm S, Kainov DE, Öhman T, Denisova OV, Schepens B et al. Phosphoproteomics to characterize host response during influenza A virus infection of human macrophages. Mol Cell Proteomics 2016; 15:3203–3219 [View Article][PubMed]
    [Google Scholar]
  47. Droebner K, Pleschka S, Ludwig S, Planz O. Antiviral activity of the MEK-inhibitor U0126 against pandemic H1N1v and highly pathogenic avian influenza virus in vitro and in vivo. Antiviral Res 2011; 92:195–203 [View Article][PubMed]
    [Google Scholar]
  48. Kumar N, Liang Y, Parslow TG, Liang Y. Receptor tyrosine kinase inhibitors block multiple steps of influenza A virus replication. J Virol 2011; 85:2818–2827 [View Article][PubMed]
    [Google Scholar]
  49. Pohl MO, von Recum-Knepper J, Rodriguez-Frandsen A, Lanz C, Yángüez E et al. Identification of Polo-like kinases as potential novel drug targets for influenza A virus. Sci Rep 2017; 7:8629 [View Article][PubMed]
    [Google Scholar]
  50. Smallwood HS, Duan S, Morfouace M, Rezinciuc S, Shulkin BL et al. Targeting metabolic reprogramming by influenza infection for therapeutic intervention. Cell Rep 2017; 19:1640–1653 [View Article][PubMed]
    [Google Scholar]
  51. Holzberg M, Boergeling Y, Schräder T, Ludwig S, Ehrhardt C. Vemurafenib limits influenza A virus propagation by targeting multiple signaling pathways. Front Microbiol 2017; 8:2426 [View Article][PubMed]
    [Google Scholar]
  52. Root CN, Wills EG, McNair LL, Whittaker GR. Entry of influenza viruses into cells is inhibited by a highly specific protein kinase C inhibitor. J Gen Virol 2000; 81:2697–2705 [View Article][PubMed]
    [Google Scholar]
  53. Harcourt JL, Haynes LM. Establishing a liquid-covered culture of polarized human airway epithelial Calu-3 cells to study host cell response to respiratory pathogens in vitro. J Vis Exp 2013 [View Article][PubMed]
    [Google Scholar]
  54. Rosales Fritz VM, Daniotti JL, Maccioni HJ. Chinese hamster ovary cells lacking GM1 and GD1a synthesize gangliosides upon transfection with human GM2 synthase. Biochim Biophys Acta 1997; 1354:153–158 [View Article][PubMed]
    [Google Scholar]
  55. Schnaar RL, Gerardy-Schahn R, Hildebrandt H. Sialic acids in the brain: gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration. Physiol Rev 2014; 94:461–518 [View Article][PubMed]
    [Google Scholar]
  56. Mitsuda T, Furukawa K, Fukumoto S, Miyazaki H, Urano T et al. Overexpression of ganglioside GM1 results in the dispersion of platelet-derived growth factor receptor from glycolipid-enriched microdomains and in the suppression of cell growth signals. J Biol Chem 2002; 277:11239–11246 [View Article][PubMed]
    [Google Scholar]
  57. Yates AJ, Saqr HE, van Brocklyn J. Ganglioside modulation of the PDGF receptor. A model for ganglioside functions. J Neurooncol 1995; 24:65–73[PubMed]
    [Google Scholar]
  58. de Donatis A, Comito G, Buricchi F, Vinci MC, Parenti A et al. Proliferation versus migration in platelet-derived growth factor signaling: the key role of endocytosis. J Biol Chem 2008; 283:19948–19956 [View Article][PubMed]
    [Google Scholar]
  59. Mitsui H, Takuwa N, Maruyama T, Maekawa H, Hirayama M et al. The MEK1-ERK map kinase pathway and the PI3-kinase-Akt pathway independently mediate anti-apoptotic signals in HepG2 liver cancer cells. Int J Cancer 2001; 92:55–62 [View Article][PubMed]
    [Google Scholar]
  60. Dong Y, Jia L, Wang X, Tan X, Xu J et al. Selective inhibition of PDGFR by imatinib elicits the sustained activation of ERK and downstream receptor signaling in malignant glioma cells. Int J Oncol 2011; 38:555–569 [View Article][PubMed]
    [Google Scholar]
  61. Fred RG, Boddeti SK, Lundberg M, Welsh N. Imatinib mesylate stimulates low-density lipoprotein receptor-related protein 1-mediated ERK phosphorylation in insulin-producing cells. Clin Sci 2015; 128:17–28 [View Article][PubMed]
    [Google Scholar]
  62. Hari SB, Merritt EA, Maly DJ. Conformation-selective ATP-competitive inhibitors control regulatory interactions and noncatalytic functions of mitogen-activated protein kinases. Chem Biol 2014; 21:628–635 [View Article][PubMed]
    [Google Scholar]
  63. Hinek A, Bodnaruk TD, Bunda S, Wang Y, Liu K. Neuraminidase-1, a subunit of the cell surface elastin receptor, desialylates and functionally inactivates adjacent receptors interacting with the mitogenic growth factors PDGF-BB and IGF-2. Am J Pathol 2008; 173:1042–1056 [View Article][PubMed]
    [Google Scholar]
  64. Park RJ, Shen H, Liu L, Liu X, Ferguson SM et al. Dynamin triple knockout cells reveal off target effects of commonly used dynamin inhibitors. J Cell Sci 2013; 126:5305–5312 [View Article][PubMed]
    [Google Scholar]
  65. Koivusalo M, Welch C, Hayashi H, Scott CC, Kim M et al. Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rac1 and Cdc42 signaling. J Cell Biol 2010; 188:547–563 [View Article][PubMed]
    [Google Scholar]
  66. Lakadamyali M, Rust MJ, Babcock HP, Zhuang X. Visualizing infection of individual influenza viruses. Proc Natl Acad Sci USA 2003; 100:9280–9285 [View Article][PubMed]
    [Google Scholar]
  67. Jastrzębski K, Zdżalik-Bielecka D, Mamińska A, Kalaidzidis Y, Hellberg C et al. Multiple routes of endocytic internalization of PDGFRβ contribute to PDGF-induced STAT3 signaling. J Cell Sci 2017; 130:577–589 [View Article][PubMed]
    [Google Scholar]
  68. Fujita A, Cheng J, Hirakawa M, Furukawa K, Kusunoki S et al. Gangliosides GM1 and GM3 in the living cell membrane form clusters susceptible to cholesterol depletion and chilling. Mol Biol Cell 2007; 18:2112–2122 [View Article][PubMed]
    [Google Scholar]
  69. Markwell MA, Fredman P, Svennerholm L. Receptor ganglioside content of three hosts for Sendai virus. MDBK, HeLa, and MDCK cells. Biochim Biophys Acta 1984; 775:7–16 [View Article][PubMed]
    [Google Scholar]
  70. Janich P, Corbeil D. GM1 and GM3 gangliosides highlight distinct lipid microdomains within the apical domain of epithelial cells. FEBS Lett 2007; 581:1783–1787 [View Article][PubMed]
    [Google Scholar]
  71. Golard A. Anti-GM3 antibodies activate calcium inflow and inhibit platelet-derived growth factor beta receptors (PDGFbetar) in T51B rat liver epithelial cells. Glycobiology 1998; 8:1221–1225[PubMed]
    [Google Scholar]
  72. de Vries E, de Vries RP, Wienholts MJ, Floris CE, Jacobs MS et al. Influenza A virus entry into cells lacking sialylated N-glycans. Proc Natl Acad Sci USA 2012; 109:7457–7462 [View Article][PubMed]
    [Google Scholar]
  73. Pleschka S, Wolff T, Ehrhardt C, Hobom G, Planz O et al. Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade. Nat Cell Biol 2001; 3:301–305 [View Article][PubMed]
    [Google Scholar]
  74. Zhu L, Ly H, Liang Y. PLC-γ1 signaling plays a subtype-specific role in postbinding cell entry of influenza A virus. J Virol 2014; 88:417–424 [View Article][PubMed]
    [Google Scholar]
  75. Marjuki H, Gornitzky A, Marathe BM, Ilyushina NA, Aldridge JR et al. Influenza A virus-induced early activation of ERK and PI3K mediates V-ATPase-dependent intracellular pH change required for fusion. Cell Microbiol 2011; 13:587–601 [View Article][PubMed]
    [Google Scholar]
  76. Sigismund S, Confalonieri S, Ciliberto A, Polo S, Scita G et al. Endocytosis and signaling: cell logistics shape the eukaryotic cell plan. Physiol Rev 2012; 92:273–366 [View Article][PubMed]
    [Google Scholar]
  77. Gosens R, Stelmack GL, Dueck G, McNeill KD, Yamasaki A et al. Role of caveolin-1 in p42/p44 MAP kinase activation and proliferation of human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2006; 291:L523–L534 [View Article][PubMed]
    [Google Scholar]
  78. Chu VC, Whittaker GR. Influenza virus entry and infection require host cell N-linked glycoprotein. Proc Natl Acad Sci USA 2004; 101:18153–18158 [View Article][PubMed]
    [Google Scholar]
  79. Chen PH, Chen X, He X. Platelet-derived growth factors and their receptors: structural and functional perspectives. Biochim Biophys Acta 2013; 1834:2176–2186 [View Article][PubMed]
    [Google Scholar]
  80. Kawashima N, Yoon SJ, Itoh K, Nakayama K. Tyrosine kinase activity of epidermal growth factor receptor is regulated by GM3 binding through carbohydrate to carbohydrate interactions. J Biol Chem 2009; 284:6147–6155 [View Article][PubMed]
    [Google Scholar]
  81. Yoon SJ, Nakayama K, Hikita T, Handa K, Hakomori SI. Epidermal growth factor receptor tyrosine kinase is modulated by GM3 interaction with N-linked GlcNAc termini of the receptor. Proc Natl Acad Sci USA 2006; 103:18987–18991 [View Article][PubMed]
    [Google Scholar]
  82. Aubert JD, Hayashi S, Hards J, Bai TR, Paré PD et al. Platelet-derived growth factor and its receptor in lungs from patients with asthma and chronic airflow obstruction. Am J Physiol 1994; 266:L655–L663 [View Article][PubMed]
    [Google Scholar]
  83. Narasimhan R, Murray RK. Neutral glycosphingolipids and gangliosides of human lung and lung tumours. Biochem J 1979; 179:199–211 [View Article][PubMed]
    [Google Scholar]
  84. Hanqing M, Avrova N, Månsson JE, Molin K, Svennerholm L. Gangliosides and neutral glycosphingolipids of normal tissue and oat cell carcinoma of human lung. Biochim Biophys Acta 1986; 878:360–370 [View Article][PubMed]
    [Google Scholar]
  85. Lewis CC, Chu HW, Westcott JY, Tucker A, Langmack EL et al. Airway fibroblasts exhibit a synthetic phenotype in severe asthma. J Allergy Clin Immunol 2005; 115:534–540 [View Article][PubMed]
    [Google Scholar]
  86. Humbert M, de Blay F, Garcia G, Prud'homme A, Leroyer C et al. Masitinib, a c-kit/PDGF receptor tyrosine kinase inhibitor, improves disease control in severe corticosteroid-dependent asthmatics. Allergy 2009; 64:1194–1201 [View Article][PubMed]
    [Google Scholar]
  87. Shaw DE, Baig F, Bruce I, Chamoin S, Collingwood SP et al. Optimization of platelet-derived growth factor receptor (PDGFR) inhibitors for duration of action, as an inhaled therapy for lung remodeling in pulmonary arterial hypertension. J Med Chem 2016; 59:7901–7914 [View Article][PubMed]
    [Google Scholar]
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