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2000
Volume 25, Issue 3
  • ISSN: 1389-5575
  • E-ISSN: 1875-5607

Abstract

Flu is an acute respiratory disease caused by influenza viruses. The influenza viruses are classified as (influenza A virus, IAV), (influenza B virus, IBV), (influenza C virus, ICV), and (influenza D virus, IDV) according to the antigenicity of nucleoproteins (NPs) and matrix (M) proteins . It is estimated that the seasonal influenza epidemics will cause about 3-5 million cases of serious illness and 290,000-650,000 deaths in the world every year, while influenza A virus is the leading cause of infection and death. Neuraminidase (NA) is one of the most critical targets for the development of anti-influenza virus drugs, and the main drugs clinically applied for the treatment of flu are neuraminidase inhibitors. However, various mutant strains have developed resistance to these inhibitors (For example, the substrains of H274Y in H1N1, H5N1, and E119V in H3N2 have developed resistance to Oseltamivir). Influenza viruses mutate frequently, and new substrains emerge constantly, and the pandemics caused by the new substrains will break out at any time. Therefore, it is urgent to develop new and wide-spectrum influenza virus inhibitors for overcoming the emerging influenza pandemic. Here, we focus on describing the progress of influenza virus inhibitors in clinics and clinical trials to provide a comprehensive reference for the researchers.

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References

  1. SmithW. AndrewesC.H. LaidlawP.P. A virus obtained from influenza patients.Lancet19332225732666810.1016/S0140‑6736(00)78541‑2
    [Google Scholar]
  2. WilsonI.A. SkehelJ.J. WileyD.C. Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 Å resolution.Nature1981289579636637310.1038/289366a0 7464906
    [Google Scholar]
  3. ColmanP.M. VargheseJ.N. LaverW.G. Structure of the catalytic and antigenic sites in influenza virus neuraminidase.Nature19833035912414410.1038/303041a0 6188957
    [Google Scholar]
  4. (aWHOInfluenza seasonal.Available from: https://www.who.int/health-topics/influenza-seasonal 2023
  5. (b ShiM. LinX.D. ChenX. TianJ.H. ChenL.J. LiK. WangW. EdenJ.S. ShenJ.J. LiuL. HolmesE.C. ZhangY.Z. The evolutionary history of vertebrate RNA viruses.Nature2018556770019720210.1038/s41586‑018‑0012‑7 29618816
    [Google Scholar]
  6. WHOHistory of influenza Pandemics.Available from: http://www.euro.who.int/influenza/20080702-9,2010-09-01
  7. WHOPandemic(H1N1)2009-update112.Available from: http://www.who.int/csr/don/2010-08 06/en/index.html 2009
  8. WebsterR.G. BeanW.J. GormanO.T. ChambersT.M. KawaokaY. Evolution and ecology of influenza A viruses.Microbiol. Rev.199256115217910.1128/mr.56.1.152‑179.1992 1579108
    [Google Scholar]
  9. (a UrbaniakK. Markowska-DanielI. In vivo reassortment of influenza viruses.Acta Biochim. Pol.201461342743110.18388/abp.2014_186025180223
    [Google Scholar]
  10. (b YoonS.W. WebbyR.J. WebsterR.G. Evolution and ecology of influenza A viruses.Curr. Top. Microbiol. Immunol.201438535937510.1007/82_2014_396 24990620
    [Google Scholar]
  11. McGeochD. FellnerP. NewtonC. Influenza virus genome consists of eight distinct RNA species.Proc. Natl. Acad. Sci.19767393045304910.1073/pnas.73.9.3045 1067600
    [Google Scholar]
  12. LambR.A. KrugR.M. Orthomyxoviridase: The viruses and their replication.Fields virology19951532
    [Google Scholar]
  13. MaedaT. KawasakiK. OhnishiS. Interaction of influenza virus hemagglutinin with target membrane lipids is a key step in virus-induced hemolysis and fusion at pH 5.2.Proc. Natl. Acad. Sci.19817874133413710.1073/pnas.78.7.4133 6945575
    [Google Scholar]
  14. HuangR.T.C. RottR. KlenkH.D. Influenza viruses cause hemolysis and fusion of cells.Virology1981110124324710.1016/0042‑6822(81)90030‑1 7210509
    [Google Scholar]
  15. WhiteJ. KielianM. HeleniusA. Membrane fusion proteins of enveloped animal viruses.Q. Rev. Biophys.198316215119510.1017/S0033583500005072 6359230
    [Google Scholar]
  16. García-SastreA. The neuraminidase of bat influenza viruses is not a neuraminidase.Proc. Natl. Acad. Sci.201210946186351863610.1073/pnas.1215857109 23100536
    [Google Scholar]
  17. CaiY.C. HuangC. KuZ.Q. HuangZ. Influenza virus vs. influenza vaccine a Nonstop over the last one hundred years.Chin. J. Nat.2009314213222
    [Google Scholar]
  18. HerfstS. SchrauwenE.J.A. LinsterM. ChutinimitkulS. de WitE. MunsterV.J. SorrellE.M. BestebroerT.M. BurkeD.F. SmithD.J. RimmelzwaanG.F. OsterhausA.D.M.E. FouchierR.A.M. Airborne transmission of influenza A/H5N1 virus between ferrets.Science201233660881534154110.1126/science.1213362 22723413
    [Google Scholar]
  19. ScholtissekC. The genes coding for the surface glycoproteins of influenza A viruses contain a small conserved and a large variable region.Virology197993259459710.1016/0042‑6822(79)90264‑2 452416
    [Google Scholar]
  20. ShihA.C.C. HsiaoT.C. HoM.S. LiW.H. Simultaneous amino acid substitutions at antigenic sites drive influenza A hemagglutinin evolution.Proc. Natl. Acad. Sci.2007104156283628810.1073/pnas.0701396104 17395716
    [Google Scholar]
  21. ScholtissekC. Source for influenza pandemics.Eur. J. Epidemiol.199410445545810.1007/BF01719674 7843354
    [Google Scholar]
  22. ScholtissekC. The genome of the influenza virus.Curr. Top. Microbiol. Immunol.197880139169 668407
    [Google Scholar]
  23. ScholtissekC. Pigs as mixing vessels for the creation of new pandemic influenza A viruses.Med. Princ. Pract.199022657110.1159/000157337
    [Google Scholar]
  24. KawaokaY. KraussS. WebsterR.G. Avian-to-human transmission of the PB1 gene of influenza A viruses in the 1957 and 1968 pandemics.J. Virol.198963114603460810.1128/jvi.63.11.4603‑4608.1989 2795713
    [Google Scholar]
  25. DaviesW.L. GrunertR.R. HaffR.F. McGahenJ.W. NeumayerE.M. PaulshockM. WattsJ.C. WoodT.R. HermannE.C. HoffmannC.E. Antiviral activity of 1-adamantanamine (amantadine).Science1964144362086286310.1126/science.144.3620.862 14151624
    [Google Scholar]
  26. PintoL.H. HolsingerL.J. LambR.A. Influenza virus M2 protein has ion channel activity.Cell199269351752810.1016/0092‑8674(92)90452‑I 1374685
    [Google Scholar]
  27. BrightR.A. MedinaM. XuX. Perez-OronozG. WallisT.R. DavisX.M. PovinelliL. CoxN.J. KlimovA.I. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: A cause for concern.Lancet200536694921175118110.1016/S0140‑6736(05)67338‑2 16198766
    [Google Scholar]
  28. LanY. LiZ. DongL.B. ZhangY. WenL.Y. ZhangY.M. WangM. GuoY.J. ShuY.L. Adamantane resistance among influenza A (H3N2) viruses isolated from the mainland of China.Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi20062022123 16816855
    [Google Scholar]
  29. SooW. Adverse effects of rimantadine: Summary from clinical trials.J. Respir. Dis.1989102631
    [Google Scholar]
  30. BelsheR.B. BurkB. NewmanF. CerrutiR.L. SimI.S. Resistance of influenza A virus to amantadine and rimantadine: Results of one decade of surveillance.J. Infect. Dis.1989159343043510.1093/infdis/159.3.430 2915166
    [Google Scholar]
  31. PaleseP. CompansR.W. Inhibition of influenza virus replication in tissue culture by 2-deoxy-2,3-dehydro-N-trifluoroacety lneuraminic acid (FANA): mechanism of action.J. Gen. Virol.197633115916310.1099/0022‑1317‑33‑1‑159 978183
    [Google Scholar]
  32. VargheseJ.N. LaverW.G. ColmanP.M. Structure of the influenza virus glycoprotein antigen neuraminidase at 2.9 Å resolution.Nature19833035912354010.1038/303035a0 6843658
    [Google Scholar]
  33. BlixG. About the carbohydrate groups of submaxillary mucin.Hoppe Seylers Z. Physiol. Chem.19362401-2435410.1515/bchm2.1936.240.1‑2.43
    [Google Scholar]
  34. MeindlP. TuppyH. 2-deoxy-2.3-dehydro-sialic acids, I: Synthesis and properties of 2-deoxy-2.3-dehydro-N-acyl-neuraminic acids and their methyl esters.Monatsh. Chem.196910041295130610.1007/BF00903465
    [Google Scholar]
  35. MeindlP. TuppyH. 2-Deoxy-2,3-dehydrosialic acids. II. Competitive inhibition of Vibrio cholerae neuraminidase by 2-deoxy-2,3-dehydro-N-acylneuraminic acids.Hoppe Seylers Z. Physiol. Chem.196935091088109210.1515/bchm2.1969.350.2.1088 5349377
    [Google Scholar]
  36. StollV. StewartK.D. MaringC.J. MuchmoreS. GirandaV. GuY. WangG. ChenY. Influenza neuram inidase inhibitors: Structure-based design of a novel inhibi tors series.Biochemistry200342371872710.1021/bi020544912534284
    [Google Scholar]
  37. Bossart-WhitakerP. CarsonM. BabuY.S. SmithC.D. LaverW.G. AirG.M. Three-dimensional structure of in fluenza A N9 neuraminidase and its complex with the in hibitor 2-deoxy 2,3-dehydro-N-acetyl neuraminic acid.J. Mol. Biol.199323241069108310.1006/jmbi.1993.1461 8371267
    [Google Scholar]
  38. TaylorN.R. von ItzsteinM. Molecular modeling studies on ligand binding to sialidase from influenza virus and the mechanism of catalysis.J. Med. Chem.199437561662410.1021/jm00031a011 8126701
    [Google Scholar]
  39. LiC.Y. Inhaled Zanamivir to prevent influenza transmission in families.Int. J. Epidemiol. Infect. Dis.20013141142
    [Google Scholar]
  40. CassL.M.R. BrownJ. PickfordM. FayinkaS. NewmanS.P. JohanssonC.J. ByeA. Pharmacoscintigraphic evaluation of lung deposition of inhaled zanamivir in healthy volunteers.Clin. Pharmacokinet.1999361213110.2165/00003088‑199936001‑00003 10429837
    [Google Scholar]
  41. CassL.M.R. EfthymiopoulosC. ByeA. Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers.Clin. Pharmacokinet.199936111110.2165/00003088‑199936001‑00001 10429835
    [Google Scholar]
  42. DanielM.J. BarnettJ.M. PearsonB.A. The low potential for drug interactions with zanamivir.Clin. Pharmacokinet.1999361415010.2165/00003088‑199936001‑00005 10429839
    [Google Scholar]
  43. KangH.L. Clinical observation and nursing of patients with influenza using inhaled Zanamivir.Clin. Nurs. Res.2011253532523253
    [Google Scholar]
  44. LiZ.R. Zanamivir, a new broad-spectrum and highly effective anti-influenza virus drug.World Notes Antibiot.200104183187
    [Google Scholar]
  45. MendelD.B. TaiC.Y. EscarpeP.A. LiW. SidwellR.W. HuffmanJ.H. SweetC. JakemanK.J. MersonJ. LacyS.A. LewW. WilliamsM.A. ZhangL. ChenM.S. BischofbergerN. KimC.U. Oral administration of a prodrug of the influenza virus neuraminidase inhibitor GS 4071 protects mice and ferrets against influenza infection.Antimicrob. Agents Chemother.199842364064610.1128/AAC.42.3.640 9517945
    [Google Scholar]
  46. LewW. ChenX. KimC.U. Discovery and development of GS 4104 (oseltamivir): An orally active influenza neuraminidase inhibitor.Curr. Med. Chem.20007666367210.2174/0929867003374886 10702632
    [Google Scholar]
  47. HeG. MassarellaJ. WardP. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802.Clin. Pharmacokinet.199937647148410.2165/00003088‑199937060‑00003 10628898
    [Google Scholar]
  48. YuJ. DaiD.Y. WangX.Y. Clinical application of two anti-influenza A (H1N1) virus drugs.China Pharm.200918166869
    [Google Scholar]
  49. HamaR. JonesM. OkushimaH. KitaoM. NodaN. HayashiK. SakaguchiK. Oseltamivir and early deterioration leading to death: A proportional mortality study for 2009A/H1N1 influenza.Int. J. Risk Saf. Med.201123420121510.3233/JRS‑2011‑0545 22156085
    [Google Scholar]
  50. GooskensJ. JongesM. ClaasE.C.J. MeijerA. van den BroekP.J. KroesA.M. Morbidity and mortality associated with nosocomial transmission of oseltamivir-resistant influenza A(H1N1) virus.JAMA2009301101042104610.1001/jama.2009.297 19255111
    [Google Scholar]
  51. LeQ.M. KisoM. SomeyaK. SakaiY.T. NguyenT.H. NguyenK.H.L. PhamN.D. NgyenH.H. YamadaS. MuramotoY. HorimotoT. TakadaA. GotoH. SuzukiT. SuzukiY. KawaokaY. Isolation of drug-resistant H5N1 virus.Nature20054377062110810.1038/4371108a 16228009
    [Google Scholar]
  52. TreanorJ.J. HaydenF.G. VroomanP.S. BarbarashR. BettisR. RiffD. SinghS. KinnersleyN. WardP. MillsR.G. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial.JAMA200028381016102410.1001/jama.283.8.1016 10697061
    [Google Scholar]
  53. BabuY.S. ChandP. BantiaS. KotianP. DehghaniA. El-KattanY. LinT.H. HutchisonT.L. ElliottA.J. ParkerC.D. AnanthS.L. HornL.L. LaverG.W. MontgomeryJ.A. BCX-1812 (RWJ-270201): discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design.J. Med. Chem.200043193482348610.1021/jm0002679 11000002
    [Google Scholar]
  54. BantiaS. ParkerC.D. AnanthS.L. HornL.L. AndriesK. ChandP. KotianP.L. DehghaniA. El-KattanY. LinT. HutchisonT.L. MontgomeryJ.A. KellogD.L. BabuY.S. Comparison of the anti-influenza virus activity of RWJ-270201 with those of oseltamivir and zanamivir.Antimicrob. Agents Chemother.20014541162116710.1128/AAC.45.4.1162‑1167.2001 11257030
    [Google Scholar]
  55. BantiaS. ArnoldC.S. ParkerC.D. UpshawR. ChandP. Anti-influenza virus activity of peramivir in mice with single intramuscular injection.Antiviral Res.2006691394510.1016/j.antiviral.2005.10.002 16325932
    [Google Scholar]
  56. LeangS.K. KwokS. SullivanS.G. Maurer-StrohS. KelsoA. BarrI.G. HurtA.C. Peramivir and laninamivir susceptibility of circulating influenza A and B viruses.Influenza Other Respir. Viruses20148213513910.1111/irv.12187 24734292
    [Google Scholar]
  57. ZhaoX. ZhouY. LuM. WangL.L. LiS. ZhangH.L. CuiY.M. Study on the tolerance of paramivir trihydrate chloride injection in healthy volunteers.Chin. J. New Drug2010192119641966
    [Google Scholar]
  58. ZhaoX. LuM. ZhangY.H. WangL.L. LiS. ZhangH.L. GuJ.K. CuiY.M. Pharmacokinetics of paramivir trihydrate sodium chloride in healthy volunteers.Chin. J. Clin. Pgarmaclo.20132910751754
    [Google Scholar]
  59. YamashitaM. TomozawaT. KakutaM. TokumitsuA. NasuH. KuboS. CS-8958, a prodrug of the new neuraminidase inhibitor R-125489, shows long-acting anti-influenza virus activity.Antimicrob. Agents Chemother.200953118619210.1128/AAC.00333‑08 18955520
    [Google Scholar]
  60. IkematsuH. KawaiN. Laninamivir octanoate: A new long-acting neuraminidase inhibitor for the treatment of influenza.Expert Rev. Anti Infect. Ther.201191085185710.1586/eri.11.112 21973296
    [Google Scholar]
  61. YamashitaM. Unique characteristics of long-acting neuraminidase inhibitor laninamivir octanoate (CS-8958) that explains its long-lasting activity.Expert Rev. Anti Infect. Ther.201159395
    [Google Scholar]
  62. WatanabeA. ChangS.C. KimM.J. ChuD.W. OhashiY. Long-acting neuraminidase inhibitor laninamivir octanoate versus oseltamivir for treatment of influenza: A double-blind, randomized, noninferiority clinical trial.Clin. Infect. Dis.201051101167117510.1086/656802 20936975
    [Google Scholar]
  63. SugayaN. OhashiY. Long-acting neuraminidase inhibitor laninamivir octanoate (CS-8958) versus oseltamivir as treatment for children with influenza virus infection.Antimicrob. Agents Chemother.20105462575258210.1128/AAC.01755‑09 20368393
    [Google Scholar]
  64. KisoM. KuboS. OzawaM. LeQ.M. NidomC.A. YamashitaM. KawaokaY. Efficacy of the new neuraminidase inhibitor CS-8958 against H5N1 influenza viruses.PLoS Pathog.201062e100078610.1371/journal.ppat.1000786 20195462
    [Google Scholar]
  65. SamsonM. AbedY. DesrochersF.M. HamiltonS. LuttickA. TuckerS.P. PryorM.J. BoivinG. Characterization of drug-resistant influenza virus A(H1N1) and A(H3N2) variants selected in vitro with laninamivir.Antimicrob. Agents Chemother.20145895220522810.1128/AAC.03313‑14 24957832
    [Google Scholar]
  66. SamsonM. PizzornoA. AbedY. BoivinG. Influenza virus resistance to neuraminidase inhibitors.Antiviral Res.201398217418510.1016/j.antiviral.2013.03.014 23523943
    [Google Scholar]
  67. YamashitaM. Laninamivir and its prodrug, CS-8958: Long-acting neuraminidase inhibitors for the treatment of influenza.Antivir. Chem. Chemother.2010212718410.3851/IMP1688 21107016
    [Google Scholar]
  68. te VelthuisA.J.W. RobbN.C. KapanidisA.N. FodorE. The role of the priming loop in influenza A virus RNA synthesis.Nat. Microbiol.2016151602910.1038/nmicrobiol.2016.29 27274864
    [Google Scholar]
  69. ReichS. GuilligayD. PflugA. MaletH. BergerI. CrépinT. HartD. LunardiT. NanaoM. RuigrokR.W.H. CusackS. Structural insight into cap-snatching and RNA synthesis by influenza polymerase.Nature2014516753136136610.1038/nature14009 25409151
    [Google Scholar]
  70. NoshiT. KitanoM. TaniguchiK. YamamotoA. OmotoS. BabaK. HashimotoT. IshidaK. KushimaY. HattoriK. KawaiM. YoshidaR. KobayashiM. YoshinagaT. SatoA. OkamatsuM. SakodaY. KidaH. ShishidoT. NaitoA. In vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit.Antiviral Res.201816010911710.1016/j.antiviral.2018.10.008 30316915
    [Google Scholar]
  71. GubarevaL.V. WebsterR.G. HaydenF.G. Detection of influenza virus resistance to neuraminidase inhibitors by an enzyme inhibition assay.Antiviral Res.2002531476110.1016/S0166‑3542(01)00192‑9 11684315
    [Google Scholar]
  72. McKimm-BreschkinJ.L. BlickT.J. SahasrabudheA. TiongT. MarshallD. HartG.J. BethellR.C. PennC.R. Generation and characterization of variants of NWS/G70C influenza virus after in vitro passage in 4-amino-Neu5Ac2en and 4-guanidino-Neu5Ac2en.Antimicrob. Agents Chemother.1996401404610.1128/AAC.40.1.40 8787876
    [Google Scholar]
  73. McKimmbreschkinJ. Resistance of influenza viruses to neuraminidase inhibitors a review.Antiviral Res.200047111710.1016/S0166‑3542(00)00103‑0 10930642
    [Google Scholar]
  74. DuJ. CrossT.A. ZhouH.X. Recent progress in structure-based anti-influenza drug design.Drug Discov. Today20121719-201111112010.1016/j.drudis.2012.06.002 22704956
    [Google Scholar]
  75. LinX. LiX. LinX. A review on applications of computational methods in drug screening and design.Molecules2020256137510.3390/molecules25061375 32197324
    [Google Scholar]
  76. von ItzsteinM. WuW.Y. KokG.B. PeggM.S. DyasonJ.C. JinB. Van PhanT. SmytheM.L. WhiteH.F. OliverS.W. ColmanP.M. VargheseJ.N. RyanD.M. WoodsJ.M. BethellR.C. HothamV.J. CameronJ.M. PennC.R. Rational design of potent sialidase-based inhibitors of influenza virus replication.Nature1993363642841842310.1038/363418a0 8502295
    [Google Scholar]
  77. FoxL.M. SaravolatzL.D. Nitazoxanide: A new thiazolide antiparasitic agent.Clin. Infect. Dis.20054081173118010.1086/428839 15791519
    [Google Scholar]
  78. BelardoG. CenciarelliO. La FraziaS. RossignolJ.F. SantoroM.G. Synergistic effect of nitazoxanide with neuraminidase inhibitors against influenza A viruses in vitro.Antimicrob. Agents Chemother.20155921061106910.1128/AAC.03947‑14 25451059
    [Google Scholar]
  79. GuskovaT.A. GlushkovR.G. Efficacy and safety of arbidol in treating and Prophylaxis of influenza: clinical trials. Arbidol : A New Antiviral, Immunomodulator, Interferon Inducer (Russian)MoscowTimotek19996375
    [Google Scholar]
  80. ShiL. XiongH. HeJ. DengH. LiQ. ZhongQ. HouW. ChengL. XiaoH. YangZ. Antiviral activity of arbidol against influenza A virus, respiratory syncytial virus, rhinovirus, coxsackie virus and adenovirus in vitro and in vivo.Arch. Virol.200715281447145510.1007/s00705‑007‑0974‑5 17497238
    [Google Scholar]
  81. ByrnR.A. JonesS.M. BennettH.B. BralC. ClarkM.P. JacobsM.D. KwongA.D. LedeboerM.W. LeemanJ.R. McNeilC.F. MurckoM.A. NezamiA. PerolaE. RijnbrandR. SaxenaK. TsaiA.W. ZhouY. CharifsonP.S. Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit.Antimicrob. Agents Chemother.20155931569158210.1128/AAC.04623‑14 25547360
    [Google Scholar]
  82. GeH. WangY.F. XuJ. GuQ. LiuH.B. XiaoP.G. ZhouJ. LiuY. YangZ. SuH. Anti-influenza agents from traditional chinese medicine.Nat. Prod. Rep.201027121758178010.1039/c0np00005a 20941447
    [Google Scholar]
  83. WangX. JiaW. ZhaoA. WangX. Anti‐influenza agents from plants and traditional Chinese medicine.Phytother. Res.200620533534110.1002/ptr.1892 16619359
    [Google Scholar]
  84. XiongY. LiN.X. DuanN. LiuB. ZhuH. ZhangC. LiL. LuC. HuangL. Traditional Chinese medicine in treating influenza: From basic science to clinical applications.Front. Pharmacol.20201157580310.3389/fphar.2020.575803 33041821
    [Google Scholar]
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