177
Views
0
CrossRef citations to date
0
Altmetric
Perspective

Identifying Novel Antiviral Targets Against Enterovirus 71: Where Are We?

&
Pages 171-191 | Received 28 Dec 2016, Accepted 02 Feb 2017, Published online: 31 Mar 2017

References

  • McMinn PC . Recent advances in the molecular epidemiology and control of human enterovirus 71 infection . Curr. Opin. Virol.2 ( 2 ), 199 – 205 ( 2012 ).
  • McMinn PC . An overview of the evolution of enterovirus 71 and its clinical and public health significance . FEMS Microbiol. Rev.26 ( 1 ), 91 – 107 ( 2002 ).
  • Solomon T , LewthwaiteP, PereraD, CardosaMJ, McMinnP, OoiMH . Virology, epidemiology, pathogenesis, and control of enterovirus 71 . Lancet Infect. Dis.10 ( 11 ), 778 – 790 ( 2010 ).
  • Cardosa MJ , PereraD, BrownBAet al. Molecular epidemiology of human enterovirus 71 strains and recent outbreaks in the Asia-Pacific region: comparative analysis of the VP1 and VP4 genes . Emerg. Infect. Dis.9 ( 4 ), 461 – 468 ( 2003 ).
  • Chang LY , KingCC, HsuKHet al. Risk factors of enterovirus 71 infection and associated hand, foot, and mouth disease/herpangina in children during an epidemic in Taiwan . Pediatrics109 ( 6 ), e88 ( 2002 ).
  • Chang LY , HuangLM, GauSSFet al. Neurodevelopment and cognition in children after enterovirus 71 infection . N. Engl. J. Med.356 ( 12 ), 1226 – 1234 ( 2007 ).
  • Chan KP , GohKT, ChongCY, TeoES, LauG, LingAE . Epidemic hand, foot and mouth disease caused by human enterovirus 71, Singapore . Emerg. Infect. Dis.9 ( 1 ), 78 – 85 ( 2003 ).
  • Wu KX , NgMML, ChuJJH . Developments towards antiviral therapies against enterovirus 71 . Drug Discov. Today15 ( 23–24 ), 1041 – 1051 ( 2010 ).
  • Zeng M , El KhatibNF, TuSet al. Seroepidemiology of Enterovirus 71 infection prior to the 2011 season in children in Shanghai . J. Clin. Virol.53 ( 4 ), 285 – 289 ( 2012 ).
  • Hsiung GD , WangJR . Enterovirus infections with special reference to enterovirus 71 . J. Microbiol. Immunol. Infect.33 ( 1 ), 1 – 8 ( 2000 ).
  • Kuo RL , ShihSR . Strategies to develop antivirals against enterovirus 71 . Virol. J.10, 28 ( 2013 ).
  • Ooi MH , WongSC, LewthwaiteP, CardosaMJ, SolomonT . Clinical features, diagnosis, and management of enterovirus 71 . Lancet Neurol.9 ( 11 ), 1097 – 1105 ( 2010 ).
  • Yang F , RenL, XiongZet al. Enterovirus 71 outbreak in the People’s Republic of China in 2008 . J. Clin. Microbiol.47 ( 7 ), 2351 – 2352 ( 2009 ).
  • Huang HI , ShihSR . Neurotropic enterovirus infections in the central nervous system . Viruses7 ( 11 ), 6051 – 6066 ( 2015 ).
  • Kok CC . Therapeutic and prevention strategies against human enterovirus 71 infection . World J. Virol.4 ( 2 ), 78 – 95 ( 2015 ).
  • Zhang W , TaoJ, YangXet al. Antiviral effects of two Ganoderma lucidum triterpenoids against enterovirus 71 infection . Biochem. Biophys. Res. Commun.449 ( 3 ), 307 – 312 ( 2014 ).
  • Wang SM . Milrinone in enterovirus 71 brain stem encephalitis . Front. Pharmacol.7, 82 ( 2016 ).
  • Chea S , ChengY-B, ChokephaibulkitKet al. Workshop on use of intravenous immunoglobulin in hand, foot and mouth disease in Southeast Asia . Emerg. Infect. Dis.21 ( 1 ), ( 2015 ).
  • Yamayoshi S , FujiiK, KoikeS . Receptors for enterovirus 71 . Emerg. Microbes Infect.3 ( 7 ), e53 ( 2014 ).
  • Bedard KM , SemlerBL . Regulation of picornavirus gene expression . Microbes Infect.6 ( 7 ), 702 – 713 ( 2004 ).
  • Thompson SR , SarnowP . Enterovirus 71 contains a type I IRES element that functions when eukaryotic initiation factor eIF4G is cleaved . Virology315 ( 1 ), 259 – 266 ( 2003 ).
  • Kok CC , PhuektesP, BekE, McMinnPC . Modification of the untranslated regions of human enterovirus 71 impairs growth in a cell-specific manner . J. Virol.86 ( 1 ), 542 – 552 ( 2011 ).
  • Rust RC , LandmannL, GosertRet al. Cellular COPII proteins are involved in production of the vesicles that form the poliovirus replication complex . J. Virol.75 ( 20 ), 9808 – 9818 ( 2001 ).
  • Tang WF , YangSY, WuBWet al. Reticulon 3 binds the 2C protein of enterovirus 71 and is required for viral replication . J. Biol. Chem.282 ( 8 ), 5888 – 5898 ( 2007 ).
  • Barton DJ , FlaneganJB . Synchronous replication of poliovirus RNA: initiation of negative-strand RNA synthesis requires the guanidine-inhibited activity of protein 2C . J. Virol.71 ( 11 ), 8482 – 8489 ( 1997 ).
  • Banerjee R , DasguptaA . Interaction of picornavirus 2C polypeptide with the viral negative-strand RNA . J. Gen. Virol.82 ( Pt 11 ), 2621 – 2627 ( 2001 ).
  • Paul AV , van BoomJH, FilippovD, WimmerE . Protein-primed RNA synthesis by purified poliovirus RNA polymerase . Nature393 ( 6682 ), 280 – 284 ( 1998 ).
  • Xiang W , CuconatiA, PaulAV, CaoX, WimmerE . Molecular dissection of the multifunctional poliovirus RNA-binding protein 3AB . RNA1 ( 9 ), 892 – 904 ( 1995 ).
  • Liu WT , KungSH, HsuYY, KuoRL . Infection with enterovirus 71 or expression of its 2A protease induces apoptotic cell death . J. Gen. Virol.83 ( 6 ), 1367 – 1376 ( 2002 ).
  • Lu CY , LeeCY, KaoCLet al. Incidence and case-fatality rates resulting from the 1998 enterovirus 71 outbreak in Taiwan . J. Med. Virol.67 ( 2 ), 217 – 223 ( 2002 ).
  • Foo DGW , AlonsoS, ChowVTK, PohCL . Passive protection against lethal enterovirus 71 infection in newborn mice by neutralizing antibodies elicited by a synthetic peptide . Microbes Infect.9 ( 11 ), 1299 – 1306 ( 2007 ).
  • Yu CK , ChenCC, ChenCLet al. Neutralizing antibody provided protection against enterovirus type 71 lethal challenge in neonatal mice . J. Biomed. Sci.7 ( 6 ), 523 – 528 ( 2000 ).
  • Foo DGW , AlonsoS, PhoonMC, RamachandranNP, ChowVTK, PohCL . Identification of neutralizing linear epitopes from the VP1 capsid protein of Enterovirus 71 using synthetic peptides . Virus Res.125 ( 1 ), 61 – 68 ( 2007 ).
  • Ku Z , YeX, ShiJ, WangX, LiuQ, HuangZ . Single neutralizing monoclonal antibodies targeting the VP1 GH loop of enterovirus 71 inhibit both virus attachment and internalization during viral entry . J. Virol.89 ( 23 ), 12084 – 12095 ( 2015 ).
  • Nishimura Y , ShimojimaM, TanoY, MiyamuraT, WakitaT, ShimizuH . Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71 . Nat. Med.15 ( 7 ), 794 – 797 ( 2009 ).
  • Yamayoshi S , YamashitaY, LiJet al. Scavenger receptor B2 is a cellular receptor for enterovirus 71 . Nat. Med.15 ( 7 ), 798 – 801 ( 2009 ).
  • Smyth MS , MartinJH . Picornavirus uncoating . Mol. Pathol.55 ( 4 ), 214 – 219 ( 2002 ).
  • Pevear DC , TullTM, SeipelME, GroarkeJM . Activity of pleconaril against enteroviruses . Antimicrob. Agents Chemother.43 ( 9 ), 2109 – 2115 ( 1999 ).
  • Shang L , XuM, YinZ . Antiviral drug discovery for the treatment of enterovirus 71 infections . Antiviral Res.97 ( 2 ), 183 – 194 ( 2013 ).
  • Rotbart HA , WebsterAD . Treatment of potentially life-threatening enterovirus infections with pleconaril . Clin. Infect. Dis.32 ( 2 ), 228 – 235 ( 2001 ).
  • Zhang G , ZhouF, GuBet al. In vitro and in vivo evaluation of ribavirin and pleconaril antiviral activity against enterovirus 71 infection . Arch. Virol.157 ( 4 ), 669 – 679 ( 2012 ).
  • De Palma AM , VliegenI, De ClercqE, NeytsJ . Selective inhibitors of picornavirus replication . Med. Res. Rev.28 ( 6 ), 823 – 884 ( 2008 ).
  • Shia KS , LiWT, ChangCMet al. Design, synthesis, and structure−activity relationship of pyridyl imidazolidinones: a novel class of potent and selective human enterovirus 71 inhibitors . J. Med. Chem.45 ( 8 ), 1644 – 1655 ( 2002 ).
  • Chen TC , LiuSC, HuangPN, ChangHY, ChernJH, ShihSR . Antiviral activity of pyridyl imidazolidinones against enterovirus 71 variants . J. Biomed. Sci.15 ( 3 ), 291 – 300 ( 2008 ).
  • Chern JH , ShiaKS, HsuTAet al. Design, synthesis, and structure-activity relationships of pyrazolo[3,4-d]pyrimidines: a novel class of potent enterovirus inhibitors . Bioorg. Med. Chem. Lett.14 ( 10 ), 2519 – 2525 ( 2004 ).
  • Chang CS , LinYT, ShihSRet al. Design, synthesis, and antipicornavirus activity of 1-[5-(4-arylphenoxy)alkyl]-3-pyridin-4-ylimidazolidin-2-one derivatives . J. Med. Chem.48 ( 10 ), 3522 – 3535 ( 2005 ).
  • Shih SR , TsaiMC, TsengSNet al. Mutation in enterovirus 71 capsid protein VP1 confers resistance to the inhibitory effects of pyridyl imidazolidinone . Antimicrob. Agents Chemother.48 ( 9 ), 3523 – 3529 ( 2004 ).
  • Shih SR , ChenSJ, HakimelahiGH, LiuHJ, TsengCT, ShiaKS . Selective human enterovirus and rhinovirus inhibitors: an overview of capsid-binding and protease-inhibiting molecules . Med. Res. Rev.24 ( 4 ), 449 – 474 ( 2004 ).
  • Kelly JT , De ColibusL, ElliottLet al. Potent antiviral agents fail to elicit genetically-stable resistance mutations in either enterovirus 71 or Coxsackievirus A16 . Antiviral Res.124, 77 – 82 ( 2015 ).
  • Buontempo PJ , CoxS, Wright-MinogueJet al. SCH 48973: a potent, broad-spectrum, antienterovirus compound . Antimicrob. Agents Chemother.41 ( 6 ), 1220 – 1225 ( 1997 ).
  • Han X , SunN, WuHet al. Identification and structure-activity relationships of diarylhydrazides as novel potent and selective human enterovirus inhibitors . J. Med. Chem.59 ( 5 ), 2139 – 2150 ( 2016 ).
  • Andries K , DewindtB, SnoeksJet al. In vitro activity of pirodavir (R 77975), a substituted phenoxy-pyridazinamine with broad-spectrum antipicornaviral activity . Antimicrob. Agents Chemother.36 ( 1 ), 100 – 107 ( 1992 ).
  • Barnard DL , HubbardVD, SmeeDFet al. In vitro activity of expanded-spectrum pyridazinyl oxime ethers related to pirodavir: novel capsid-binding inhibitors with potent antipicornavirus activity . Antimicrob. Agents Chemother.48 ( 5 ), 1766 – 1772 ( 2004 ).
  • Watson KG , BrownRN, CameronRet al. An orally bioavailable oxime ether capsid binder with potent activity against human rhinovirus . J. Med. Chem.46 ( 15 ), 3181 – 3184 ( 2003 ).
  • Lin TY , ChuC, ChiuCH . Lactoferrin inhibits enterovirus 71 infection of human embryonal rhabdomyosarcoma cells in vitro . J. Infect. Dis.186 ( 8 ), 1161 – 1164 ( 2002 ).
  • Weng T , ChenL, ShyuHet al. Lactoferrin inhibits enterovirus 71 infection by binding to VP1 protein and host cells . Antiviral Res.67 ( 1 ), 31 – 37 ( 2005 ).
  • Legrand D , VigiéK, SaidEAet al. Surface nucleolin participates in both the binding and endocytosis of lactoferrin in target cells . Eur. J. Biochem.271 ( 2 ), 303 – 317 ( 2004 ).
  • Marchetti M , TrybalaE, SupertiF, JohanssonM, BergströmT . Inhibition of herpes simplex virus infection by lactoferrin is dependent on interference with the virus binding to glycosaminoglycans . Virology318 ( 1 ), 405 – 413 ( 2004 ).
  • Van der Strate BW , BeljaarsL, MolemaG, HarmsenMC, MeijerDK . Antiviral activities of lactoferrin . Antiviral Res.52 ( 3 ), 225 – 239 ( 2001 ).
  • Jenssen H , AndersenJH, Uhlin-HansenL, GuttebergTJ, RekdalØ . Anti-HSV activity of lactoferricin analogues is only partly related to their affinity for heparan sulfate . Antiviral Res.61 ( 2 ), 101 – 109 ( 2004 ).
  • Arita M , WakitaT, ShimizuH . Characterization of pharmacologically active compounds that inhibit poliovirus and enterovirus 71 infectivity . J. Gen. Virol.89 ( 10 ), 2518 – 2530 ( 2008 ).
  • Wang Y , QingJ, SunY, RaoZ . Suramin inhibits EV71 infection . Antiviral Res.103, 1 – 6 ( 2014 ).
  • Huther A , DietrichU . The emergence of peptides as therapeutic drugs for the inhibition of HIV-1 . AIDS Rev.9 ( 4 ), 208 – 217 ( 2007 ).
  • Tan CW , ChanYF, SimKM, TanEL, PohCL . Inhibition of enterovirus 71 (EV-71) infections by a novel antiviral peptide derived from EV-71 capsid protein VP1 . PLoS ONE7 ( 5 ), e34589 ( 2012 ).
  • Kajiwara K , WatanabeK, TokiwaRet al. Bioorganic synthesis of a recombinant HIV-1 fusion inhibitor, SC35EK, with an N-terminal pyroglutamate capping group . Bioorg. Med. Chem.17 ( 23 ), 7964 – 7970 ( 2009 ).
  • Weng KF , LiML, HungCT, ShihSR . Enterovirus 71 3C protease cleaves a novel target CstF-64 and inhibits cellular polyadenylation . PLoS Pathog.5 ( 9 ), e1000593 ( 2009 ).
  • Li ML , HsuTA, ChenTCet al. The 3C protease activity of enterovirus 71 induces human neural cell apoptosis . Virology293 ( 2 ), 386 – 395 ( 2002 ).
  • Patick AK . Rhinovirus chemotherapy . Antiviral Res.71 ( 2–3 ), 391 – 396 ( 2006 ).
  • Lee JC , ShihSR, ChangTYet al. A mammalian cell-based reverse two-hybrid system for functional analysis of 3C viral protease of human enterovirus 71 . Anal. Biochem.375 ( 1 ), 115 – 123 ( 2008 ).
  • Lu G , QiJ, ChenZet al. Enterovirus 71 and coxsackievirus A16 3C proteases: binding to rupintrivir and their substrates and anti-hand, foot, and mouth disease virus drug design . J. Virol.85 ( 19 ), 10319 – 10331 ( 2011 ).
  • Tsai MT , ChengYH, LiuYN, LiaoNC, LuWW, KungSH . Real-time monitoring of human enterovirus (HEV)-infected cells and anti-HEV 3C protease potency by fluorescence resonance energy transfer . Antimicrob. Agents Chemother.53 ( 2 ), 748 – 755 ( 2009 ).
  • Zhang X , SongZ, QinBet al. Rupintrivir is a promising candidate for treating severe cases of enterovirus-71 infection: evaluation of antiviral efficacy in a murine infection model . Antiviral Res.97 ( 3 ), 264 – 269 ( 2013 ).
  • Kuo CJ , ShieJJ, FangJMet al. Design, synthesis, and evaluation of 3C protease inhibitors as anti-enterovirus 71 agents . Bioorganic Med. Chem.16 ( 15 ), 7388 – 7398 ( 2008 ).
  • Patick AK , BrothersMA, MaldonadoFet al. In vitro antiviral activity and single-dose pharmacokinetics in humans of a novel, orally bioavailable inhibitor of human rhinovirus 3C protease . Antimicrob. Agents Chemother.49 ( 6 ), 2267 – 2275 ( 2005 ).
  • Ang MJ , LauQY, NgFMet al. Peptidomimetic ethyl propenoate covalent inhibitors of the enterovirus 71 3C protease: a P2-P4 study . J. Enzym. Inhib. Med. Chem.31 ( 2 ), 1 – 8 ( 2015 ).
  • Tan YW , AngMJY, LauQYet al. Antiviral activities of peptide-based covalent inhibitors of the enterovirus 71 3C protease . Sci. Rep.6, 33663 ( 2016 ).
  • Zhai Y , MaY, MaFet al. Structure–activity relationship study of peptidomimetic aldehydes as enterovirus 71 3C protease inhibitors . Eur. J. Med. Chem.124, 559 – 573 ( 2016 ).
  • Zeng D , MaY, ZhangRet al. Synthesis and structure-activity relationship of α-keto amides as enterovirus 71 3C protease inhibitors . Bioorg. Med. Chem. Lett.26 ( 7 ), 1762 – 1766 ( 2016 ).
  • Wang Y , YangB, ZhaiY, YinZ, SunY, RaoZ . Peptidyl aldehyde NK-1.8k suppresses enterovirus 71 and enterovirus 68 infection by targeting protease 3C . Antimicrob. Agents Chemother.59 ( 5 ), 2636 – 2646 ( 2015 ).
  • Ma GH , YeY, ZhangDet al. Identification and biochemical characterization of DC07090 as a novel potent small molecule inhibitor against human enterovirus 71 3C protease by structure-based virtual screening . Eur. J. Med. Chem.124, 981 – 991 ( 2016 ).
  • Lin YJ , ChangYC, HsiaoNWet al. Fisetin and rutin as 3C protease inhibitors of enterovirus A71 . J. Virol. Methods182 ( 1–2 ), 93 – 98 ( 2012 ).
  • Cao Z , DingY, KeZet al. Luteoloside acts as 3C protease inhibitor of enterovirus 71 in vitro . PLoS ONE11 ( 2 ), e0148693 ( 2016 ).
  • Wang J , ZhangT, DuJ, CuiS, YangF, JinQ . Anti-enterovirus 71 effects of chrysin and its phosphate ester . PLoS ONE9 ( 3 ), e89668 ( 2014 ).
  • Song JH , KwonBE, JangHet al. Antiviral activity of chrysin derivatives against coxsackievirus B3 in vitro and in vivo . Biomol. Ther.23 ( 5 ), 465 – 470 ( 2015 ).
  • Baxter NJ , RoetzerA, LiebigHDet al. Structure and dynamics of coxsackievirus B4 2A proteinase, an enyzme involved in the etiology of heart disease . J. Virol.80 ( 3 ), 1451 – 1462 ( 2006 ).
  • Petersen JFW , CherneyMM, LiebigHD, SkernT, KuechlerE, JamesMNG . The structure of the 2A proteinase from a common cold virus: a proteinase responsible for the shut-off of host-cell protein synthesis . EMBO J.18 ( 20 ), 5463 – 5475 ( 1999 ).
  • Falah N , MontserretR, LelogeaisVet al. Blocking human enterovirus 71 replication by targeting viral 2A protease . J. Antimicrob. Chemother.67 ( 12 ), 2865 – 2869 ( 2012 ).
  • Guo Y , WangY, CaoLet al. A conserved inhibitory mechanism of a lycorine derivative against enterovirus and hepatitis C virus . Antimicrob. Agents Chemother.60 ( 2 ), 913 – 924 ( 2016 ).
  • Liu J , YangY, XuY, MaC, QinC, ZhangL . Lycorine reduces mortality of human enterovirus 71-infected mice by inhibiting virus replication . Virol. J.8 ( 1 ), 483 ( 2011 ).
  • Adams P , KandiahE, EffantinG, StevenAC, EhrenfeldE . Poliovirus 2C protein forms homo-oligomeric structures required for ATPase activity . J. Biol. Chem.284 ( 33 ), 22012 – 22021 ( 2009 ).
  • Rodríguez PL , CarrascoL . Poliovirus protein 2C has ATPase and GTPase activities . J. Biol. Chem.268 ( 11 ), 8105 – 8110 ( 1993 ).
  • Banerjee R , EcheverriA, DasguptaA . Poliovirus-encoded 2C polypeptide specifically binds to the 3′-terminal sequences of viral negative-strand RNA . J. Virol.71 ( 12 ), 9570 – 9578 ( 1997 ).
  • Vance LM , MoscufoN, ChowM, HeinzBA . Poliovirus 2C region functions during encapsidation of viral RNA . J. Virol.71 ( 11 ), 8759 – 8765 ( 1997 ).
  • Shimizu H , AgohM, AgohYet al. Mutations in the 2C region of poliovirus responsible for altered sensitivity to benzimidazole derivatives . J. Virol.74 ( 9 ), 4146 – 4154 ( 2000 ).
  • De Palma AM , HeggermontW, LankeKet al. The thiazolobenzimidazole TBZE-029 inhibits enterovirus replication by targeting a short region immediately downstream from motif C in the nonstructural protein 2C . J. Virol.82 ( 10 ), 4720 – 4730 ( 2008 ).
  • Caliguiri LA , TammI . Distribution and translation of poliovirus RNA in guanidine-treated cells . Virology36 ( 2 ), 223 – 231 ( 1968 ).
  • Caliguiri LA , TammI . Action of guanidine on the replication of poliovirus RNA . Virology35 ( 3 ), 408 – 417 ( 1968 ).
  • Loddo B , FerrariW, BrotzuG, SpaneddaA . In vitro inhibition of infectivity of polio viruses by guanidine . Nature193, 97 – 98 ( 1962 ).
  • Rightsel WA , DiceJR, McalpineRJet al. Antiviral effect of guanidine . Science134 ( 3478 ), 558 – 559 ( 1961 ).
  • Herrmann EC , HerrmannJA, DelongDC . Prevention of death in mice infected with coxsackievirus A16 using guanidine hcl mixed with substituted benzimidazoles . Antiviral Res.2 ( 6 ), 339 – 346 ( 1982 ).
  • Saunders K , KingAM, McCahonD, NewmanJW, SladeWR, ForssS . Recombination and oligonucleotide analysis of guanidine-resistant foot-and-mouth disease virus mutants . J. Virol.56 ( 3 ), 921 – 929 ( 1985 ).
  • Sadeghipour S , BekEJ, McMinnPC . Selection and characterisation of guanidine-resistant mutants of human enterovirus 71 . Virus Res.169 ( 1 ), 72 – 79 ( 2012 ).
  • Bienz K , EggerD, TroxlerM, PasamontesL . Structural organization of poliovirus RNA replication is mediated by viral proteins of the P2 genomic region . J. Virol.64 ( 3 ), 1156 – 1163 ( 1990 ).
  • Wessels E , DuijsingsD, NotebaartRAet al. A proline-rich region in the coxsackievirus 3A protein is required for the protein to inhibit endoplasmic reticulum-to-golgi transport . J. Virol.79 ( 8 ), 5163 – 5173 ( 2005 ).
  • Taylor MP , BurgonTB, KirkegaardK, JacksonWT . Role of microtubules in extracellular release of poliovirus . J. Virol.83 ( 13 ), 6599 – 6609 ( 2009 ).
  • Belov GA , EhrenfeldE . Involvement of cellular membrane traffic proteins in poliovirus replication . Cell Cycle6 ( 1 ), 36 – 38 ( 2007 ).
  • Paul AV , CaoX, HarrisKS, LamaJ, WimmerE . Studies with poliovirus polymerase 3Dpol: stimulation of poly(U) synthesis in vitro by purified poliovirus protein 3AB . J. Biol. Chem.269 ( 46 ), 29173 – 29181 ( 1994 ).
  • De Palma AM , PürstingerG, WimmerEet al. Potential use of antiviral agents in polio eradication . Emerg. Infect. Dis.14 ( 4 ), 545 – 551 ( 2008 ).
  • Heinz BA , VanceLM . Sequence determinants of 3A-mediated resistance to enviroxime in rhinoviruses and enteroviruses . J. Virol.70 ( 7 ), 4854 – 4857 ( 1996 ).
  • Heinz BA , VanceLM . The antiviral compound enviroxime targets the 3A coding region of rhinovirus and poliovirus . J. Virol.69 ( 7 ), 4189 – 4197 ( 1995 ).
  • De Palma AM , ThibautHJ, Van Der LindenLet al. Mutations in the nonstructural protein 3A confer resistance to the novel enterovirus replication inhibitor TTP-8307 . Antimicrob. Agents Chemother.53 ( 5 ), 1850 – 1857 ( 2009 ).
  • Phillpotts RJ , WallaceJ, TyrrellDAJ, TagartVB . Therapeutic activity of enviroxime against rhinovirus infection in volunteers . Antimicrob. Agents Chemother.23 ( 5 ), 671 – 675 ( 1983 ).
  • Victor F , BrownTJ, CampanaleKet al. Synthesis, antiviral activity, and biological properties of vinylacetylene analogs of enviroxime . J. Med. Chem.40 ( 10 ), 1511 – 1518 ( 1997 ).
  • Arita M , WakitaT, ShimizuH . Cellular kinase inhibitors that suppress enterovirus replication have a conserved target in viral protein 3A similar to that of enviroxime . J. Gen. Virol.90 ( 8 ), 1869 – 1879 ( 2009 ).
  • Arita M , TakebeY, WakitaT, ShimizuH . A bifunctional anti-enterovirus compound that inhibits replication and the early stage of enterovirus 71 infection . J. Gen. Virol.91 ( 11 ), 2734 – 2744 ( 2010 ).
  • Tan CW , LaiJKF, SamI-C, ChanYF . Recent developments in antiviral agents against enterovirus 71 infection . J. Biomed. Sci.21 ( 1 ), 14 ( 2014 ).
  • Gao Q , YuanS, ZhangCet al. Discovery of itraconazole with broad-spectrum in vitro antienterovirus activity that targets nonstructural protein 3A . Antimicrob. Agents Chemother.59 ( 5 ), 2654 – 2665 ( 2015 ).
  • Ypma-Wong MF , DewaltPG, JohnsonVH, LambJG, SemlerBL . Protein 3CD is the major poliovirus proteinase responsible for cleavage of the p1 capsid precursor . Virology166 ( 1 ), 265 – 270 ( 1988 ).
  • Xiang W , HarrisKS, AlexanderL, WimmerE . Interaction between the 5′-terminal cloverleaf and 3AB/3CDpro of poliovirus is essential for RNA replication . J. Virol.69 ( 6 ), 3658 – 3667 ( 1995 ).
  • Goris N , De PalmaA, ToussaintJ-F, MuschI, NeytsJ, De ClercqK . 2′-C-methylcytidine as a potent and selective inhibitor of the replication of foot-and-mouth disease virus . Antiviral Res.73 ( 3 ), 161 – 168 ( 2007 ).
  • Graci JD , TooK, SmidanskyEDet al. Lethal mutagenesis of picornaviruses with N-6-modified purine nucleoside analogues . Antimicrob. Agents Chemother.52 ( 3 ), 971 – 979 ( 2008 ).
  • Harki DA , GraciJD, GalarragaJE, ChainWJ, CameronCE, PetersonBR . Synthesis and antiviral activity of 5-substituted cytidine analogues: Identification of a potent inhibitor of viral RNA-dependent RNA polymerases . J. Med. Chem.49 ( 21 ), 6166 – 6169 ( 2006 ).
  • Kishimoto C , CrumpackerCS, AbelmannWH . Ribavirin treatment of murine coxsackievirus B3 myocarditis with analyses of lymphocyte subsets . J. Am. Coll. Cardiol.12 ( 5 ), 1334 – 1341 ( 1988 ).
  • Sun J , EnnisJ, TurnerJD, ChuJJH . Single dose of an adenovirus vectored mouse interferon-α protects mice from lethal EV71 challenge . Antiviral Res.134, 207 – 215 ( 2016 ).
  • De Lédinghen V , TrimouletP, WinnockMet al. Daily or three times a week interferon alfa-2b in combination with ribavirin or interferon alone for the treatment of patients with chronic hepatitis C . J. Hepatol.36 ( 5 ), 672 – 680 ( 2002 ).
  • Wyde PR . Respiratory syncytial virus (RSV) disease and prospects for its control . Antiviral Res.39 ( 2 ), 63 – 79 ( 1998 ).
  • Crotty S , AndinoR . Implications of high RNA virus mutation rates: Lethal mutagenesis and the antiviral drug ribavirin . Microbes Infect.4 ( 13 ), 1301 – 1307 ( 2002 ).
  • Li ZH , LiC, LingPet al. Ribavirin reduces mortality in enterovirus 71-infected mice by decreasing viral replication . J. Infect. Dis.197 ( 6 ), 854 – 857 ( 2008 ).
  • Deng CL , YeoH, YeHQet al. Inhibition of enterovirus 71 by adenosine analog NITD008 . J. Virol.88 ( 20 ), 11915 – 11923 ( 2014 ).
  • Yin Z , ChenYL, SchulWet al. An adenosine nucleoside inhibitor of dengue virus . Proc. Natl Acad. Sci. USA106 ( 48 ), 20435 – 20439 ( 2009 ).
  • Chen TC , ChangHY, LinPFet al. Novel antiviral agent DTriP-22 targets RNA-dependent RNA polymerase of enterovirus 71 . Antimicrob. Agents Chemother.53 ( 7 ), 2740 – 2747 ( 2009 ).
  • Chen Y , Bopda-WaffoA, BasuAet al. Characterization of aurintricarboxylic acid as a potent hepatitis C virus replicase inhibitor . Antivir. Chem. Chemother.20 ( 1 ), 19 – 36 ( 2009 ).
  • De Clercq E . Potential antivirals and antiviral strategies against SARS coronavirus infections . Expert Rev. Anti. Infect. Ther.4 ( 2 ), 291 – 302 ( 2006 ).
  • Santhosh KC , PaulGC, De ClercqEet al. Correlation of anti-HIV activity with anion spacing in a series of cosalane analogues with extended polycarboxylate pharmacophores . J. Med. Chem.44 ( 5 ), 703 – 714 ( 2001 ).
  • Witvrouw M , FikkertV, PluymersWet al. Polyanionic (i.e., polysulfonate) dendrimers can inhibit the replication of human immunodeficiency virus by interfering with both virus adsorption and later steps (reverse transcriptase/integrase) in the virus replicative cycle . Mol. Pharmacol.58 ( 5 ), 1100 – 1108 ( 2000 ).
  • Yap Y , ZhangX, AndonovA, HeR . Structural analysis of inhibition mechanisms of Aurintricarboxylic Acid on SARS-CoV polymerase and other proteins . Comput. Biol. Chem.29 ( 3 ), 212 – 219 ( 2005 ).
  • Hung HC , ChenTC, FangMYet al. Inhibition of enterovirus 71 replication and the viral 3D polymerase by aurintricarboxylic acid . J. Antimicrob. Chemother.65 ( 4 ), 676 – 683 ( 2010 ).
  • Li X , LiuY, WuTet al. The antiviral effect of baicalin on enterovirus 71 in vitro . Viruses7 ( 8 ), 4756 – 4771 ( 2015 ).
  • Cheng Y , PingJ, XuHD, FuHJ, ZhouZH . Synergistic effect of a novel oxymatrine-baicalin combination against hepatitis B virus replication, alpha smooth muscle actin expression and type I collagen synthesis in vitro . World J. Gastroenterol.12 ( 32 ), 5153 – 5159 ( 2006 ).
  • Hour MJ , HuangSH, ChangCYet al. Baicalein, ethyl acetate, and chloroform extracts of Scutellaria baicalensis inhibit the neuraminidase activity of pandemic 2009 H1N1 and seasonal influenza A viruses . Evid. Based Complement. Altern. Med.2013, 1 – 11 ( 2013 ).
  • Li BQ , FuT, DongyanY, MikovitsJA, RuscettiFW, WangJM . Flavonoid baicalin inhibits HIV-1 infection at the level of viral entry . Biochem. Biophys. Res. Commun.276 ( 2 ), 534 – 538 ( 2000 ).
  • Wan Q , WangH, HanXet al. Baicalin inhibits TLR7/MYD88 signaling pathway activation to suppress lung inflammation in mice infected with influenza A virus . Biomed. Rep.2 ( 3 ), 437 – 441 ( 2014 ).
  • Xu XF , CaiBL, GuanSMet al. Baicalin induces human mucoepidermoid carcinoma Mc3 cells apoptosis in vitro and in vivo . Invest. New Drugs29 ( 4 ), 637 – 645 ( 2011 ).
  • Velu AB , ChenGW, HsiehPTet al. BPR-3P0128 inhibits RNA-dependent RNA polymerase elongation and VPg uridylylation activities of Enterovirus 71 . Antiviral Res.112, 18 – 25 ( 2014 ).
  • Roehr B . Fomivirsen approved for CMV retinitis . J. Int. Assoc. Physicians AIDS Care4 ( 10 ), 14 – 16 ( 1998 ).
  • Rayburn ER , ZhangR . Antisense, RNAi, and gene silencing strategies for therapy: mission possible or impossible?Drug Discov. Today.13 ( 11–12 ), 513 – 521 ( 2008 ).
  • Haasnoot J , WesterhoutEM, BerkhoutB . RNA interference against viruses: strike and counterstrike . Nat. Biotechnol.25 ( 12 ), 1435 – 1443 ( 2007 ).
  • Gitlin L , KarelskyS, AndinoR . Short interfering RNA confers intracellular antiviral immunity in human cells . Nature418, 430 – 434 ( 2002 ).
  • Jacque JM , TriquesK, StevensonM . Modulation of HIV-1 replication by RNA interference . Nature418 ( 6896 ), 435 – 438 ( 2002 ).
  • Kapadia SB , Brideau-AndersenA, ChisariFV . Interference of hepatitis C virus RNA replication by short interfering RNAs . Proc. Natl Acad. Sci. USA100 ( 4 ), 2014 – 2018 ( 2003 ).
  • Novina CD , MurrayMF, DykxhoornDMet al. siRNA-directed inhibition of HIV-1 infection . Nat. Med.8 ( 7 ), 681 – 686 ( 2002 ).
  • Lu WW , HsuYY, YangJY, KungSH . Selective inhibition of enterovirus 71 replication by short hairpin RNAs . Biochem. Biophys. Res. Commun.325 ( 2 ), 494 – 499 ( 2004 ).
  • Tan EL , TanTMC, Tak Kwong ChowV, PohCL . Inhibition of enterovirus 71 in virus-infected mice by RNA interference . Mol. Ther.15 ( 11 ), 1931 – 1938 ( 2007 ).
  • Jones D . The long march of antisense . Nat. Rev. Drug Discov.10 ( 6 ), 401 – 402 ( 2011 ).
  • Tan CW , ChanYF, QuahYW, PohCL . Inhibition of enterovirus 71 infection by antisense octaguanidinium dendrimer-conjugated morpholino oligomers . Antiviral Res.107 ( 1 ), 35 – 41 ( 2014 ).
  • Jang SK , KräusslichHG, NicklinMJ, DukeGM, PalmenbergAC, WimmerE . A segment of the 5′ nontranslated region of encephalomyocarditis virus RNA directs internal entry of ribosomes during in vitro translation . J. Virol.62 ( 8 ), 2636 – 2643 ( 1988 ).
  • Pelletier J , SonenbergN . Internal initiation of translation of eukaryotic mRNA directed by a sequence derived from poliovirus RNA . Nature334 ( 6180 ), 320 – 325 ( 1988 ).
  • Martínez-Salas E . The impact of RNA structure on picornavirus IRES activity . Trends Microbiol.16 ( 5 ), 230 – 237 ( 2008 ).
  • Borman AM , KirchwegerR, ZieglerE, RhoadsRE, SkernT, KeanKM . elF4G and its proteolytic cleavage products: effect on initiation of protein synthesis from capped, uncapped, and IRES-containing mRNAs . RNA3 ( 2 ), 186 – 196 ( 1997 ).
  • Chen Y , ZengS, HsuJTet al. Amantadine as a regulator of internal ribosome entry site . Acta Pharmacol. Sin.29 ( 11 ), 1327 – 1333 ( 2008 ).
  • Cole JL . Activation of PKR: an open and shut case?Trends Biochem. Sci.32 ( 2 ), 57 – 62 ( 2007 ).
  • Sugrue RJ , HayAJ . Structural characteristics of the M2 protein of influenza A viruses: evidence that it forms a tetrameric channel . Virology180 ( 2 ), 617 – 624 ( 1991 ).
  • Smith JP , RileyTR, DevenyiA, BingamanSI, KunselmanA . Amantadine therapy for chronic hepatitis C . J. Gen. Intern. Med.19 ( 6 ), 662 – 668 ( 2004 ).
  • Wang J , DuJ, WuZ, JinQ . Quinacrine impairs enterovirus 71 RNA replication by preventing binding of polypyrimidine-tract binding protein with internal ribosome entry sites . PLoS ONE8 ( 1 ), e52954 ( 2013 ).
  • Malina A , KhanS, CarlsonCBet al. Inhibitory properties of nucleic acid-binding ligands on protein synthesis . FEBS Lett.579 ( 1 ), 79 – 89 ( 2005 ).
  • Gasparian AV , NeznanovN, JhaSet al. Inhibition of encephalomyocarditis virus and poliovirus replication by quinacrine: implications for the design and discovery of novel antiviral drugs . J. Virol.84 ( 18 ), 9390 – 9397 ( 2010 ).
  • Gao M , DuanH, LiuJet al. The multi-targeted kinase inhibitor sorafenib inhibits enterovirus 71 replication by regulating IRES-dependent translation of viral proteins . Antiviral Res.106 ( 1 ), 80 – 85 ( 2014 ).
  • Tung WH , HsiehHL, YangCM . Enterovirus 71 induces COX-2 expression via MAPKs, NF-κB, and AP-1 in SK-N-SH cells: role of PGE2 in viral replication . Cell. Signal.22 ( 2 ), 234 – 246 ( 2010 ).
  • Hou HY , LuWW, WuKY, LinCW, KungSH . Idarubicin is a broad-spectrum enterovirus replication inhibitor that selectively targets the virus internal ribosomal entry site . J. Gen. Virol.97 ( 5 ), 1122 – 1133 ( 2016 ).
  • Lin YJ , LaiCC, LaiCHet al. Inhibition of enterovirus 71 infections and viral IRES activity by Fructus gardeniae and geniposide . Eur. J. Med. Chem.62, 206 – 213 ( 2013 ).
  • Chung YC , HsiehFC, LinYJet al. Magnesium lithospermate B and rosmarinic acid, two compounds present in Salvia miltiorrhiza, have potent antiviral activity against enterovirus 71 infections . Eur. J. Pharmacol.755, 127 – 133 ( 2015 ).
  • Qian S , FanW, QianPet al. Apigenin restricts FMDV infection and inhibits viral IRES driven translational activity . Viruses7 ( 4 ), 1613 – 1626 ( 2015 ).
  • Lv X , QiuM, ChenD, ZhengN, JinY, WuZ . Apigenin inhibits enterovirus 71 replication through suppressing viral IRES activity and modulating cellular JNK pathway . Antiviral Res.109 ( 1 ), 30 – 41 ( 2014 ).
  • Shukla S , GuptaS . Molecular targets for apigenin-induced cell cycle arrest and apoptosis in prostate cancer cell xenograft . Mol. Cancer Ther.5 ( 4 ), 843 – 852 ( 2006 ).
  • Wang J , LiuYT, XiaoL, ZhuL, WangQ, YanT . Anti-inflammatory effects of apigenin in lipopolysaccharide-induced inflammatory in acute lung injury by suppressing COX-2 and NF-kB pathway . Inflammation37 ( 6 ), 2085 – 2090 ( 2014 ).
  • Zhang X , WangG, GurleyEC, ZhouH . Flavonoid apigenin inhibits lipopolysaccharide-induced inflammatory response through multiple mechanisms in Macrophages . PLoS ONE9 ( 9 ), e107072 ( 2014 ).
  • Zhang W , QiaoH, LvYet al. Apigenin inhibits enterovirus-71 infection by disrupting viral RNA association with trans-acting factors . PLoS ONE9 ( 10 ), e110429 ( 2014 ).
  • Ahmed-Belkacem A , GuichouJF, BrilletRet al. Inhibition of RNA binding to hepatitis C virus RNA-dependent RNA polymerase: a new mechanism for antiviral intervention . Nucleic Acids Res.42 ( 14 ), 9399 – 9409 ( 2014 ).
  • Shibata C , OhnoM, OtsukaMet al. The flavonoid apigenin inhibits hepatitis C virus replication by decreasing mature microRNA122 levels . Virology462–463 ( 1 ), 42 – 48 ( 2014 ).
  • Critchfield JW , ButeraST, FolksTM . Inhibition of HIV activation in latently infected cells by flavonoid compounds . AIDS Res. Hum. Retroviruses12 ( 1 ), 39 – 46 ( 1996 ).
  • Kanerva A , RakiM, RankiTet al. Chlorpromazine and apigenin reduce adenovirus replication and decrease replication associated toxicity . J. Gene Med.9 ( 1 ), 3 – 9 ( 2007 ).
  • Deng JX , NieXJ, LeiYFet al. The highly conserved 5′ untranslated region as an effective target towards the inhibition of Enterovirus 71 replication by unmodified and appropriate 2′- modified siRNAs . J. Biomed. Sci.19 ( 1 ), 73 ( 2012 ).
  • Liu J , ZhouZ, LiK, HanM, YangJ, WangS . In vitro and in vivo protection against enterovirus 71 by an antisense phosphorothioate oligonucleotide . Arch. Virol.159 ( 9 ), 2339 – 2347 ( 2014 ).
  • Cheung YY , ChenKC, ChenH, SengEK, ChuJJH . Antiviral activity of lanatoside C against dengue virus infection . Antiviral Res.111, 93 – 99 ( 2014 ).
  • Tan YW , HongWJ, ChuJJH . Inhibition of enterovirus VP4 myristoylation is a potential antiviral strategy for hand, foot and mouth disease . Antiviral Res.133, 191 – 195 ( 2016 ).
  • Leong SY , OngBKT, ChuJJH . The role of Misshapen NCK-related kinase (MINK), a novel Ste20 family kinase, in the IRES-mediated protein translation of human enterovirus 71 . PLoS Pathog.11 ( 3 ), 1 – 33 ( 2015 ).
  • Wu KX , PhuektesP, KumarPet al. Human genome-wide RNAi screen reveals host factors required for enterovirus 71 replication . Nat. Commun.7, 13150 ( 2016 ).
  • Thibaut HJ , LeyssenP, PuerstingerG, MuiggA, NeytsJ, De PalmaAM . Towards the design of combination therapy for the treatment of enterovirus infections . Antiviral Res.90 ( 3 ), 213 – 217 ( 2011 ).
  • Kang H , KimC, KimDEet al. Synergistic antiviral activity of gemcitabine and ribavirin against enteroviruses . Antiviral Res.124, 1 – 10 ( 2015 ).
  • Weng KF , ChenLL, HuangPN, ShihSR . Neural pathogenesis of enterovirus 71 infection . Microbes Infect.12 ( 7 ), 505 – 510 ( 2010 ).
  • Chen CS , YaoYC, LinSCet al. Retrograde axonal transport: a major transmission route of enterovirus 71 in mice . J. Virol.81 ( 17 ), 8996 – 9003 ( 2007 ).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.