title: Synergistic inhibition of enterovirus 71 replication by interferon and rupintrivir.
abstract: BACKGROUND
  Enterovirus 71 (EV71) can cause severe diseases and even lead to death in children. There is no vaccine or specific antiviral therapy to prevent or cure EV71 infection. Although interferon (IFN)-α has been used in the treatment of several viral infections, we found that IFN-α alone was ineffective in restricting EV71 replication in Vero cells.
  
  
  METHODS
  Through a bioinformatics analysis, several cellular proteins in the IFN response pathway were identified as susceptible substrates that might be degraded by the EV71-encoded 3C protease (3C(pro)).
  
  
  RESULTS
  Indeed, IRF9 was shown to be vulnerable to 3C(pro) cleavage, as revealed by enzyme-based and cell-based assays. Thus, the IFN-mediated antiviral mechanism compromised by the viral 3C(pro) in EV71-infected cells may be accountable, at least partially, for that IFN-α cannot inhibit EV71 replication. Because rupintrivir (AG7088) is known to be an effective EV71 inhibitor, we investigated the effects of the combination of rupintrivir and IFN-α on EV71 replication and found that they strongly synergized with each other in inhibiting EV71 replication.
  
  
  CONCLUSIONS
  Because rupintrivir was shown to be generally tolerable in earlier clinical investigations, it is worth evaluating whether a combination of rupintrivir and IFN-α could be an effective treatment for EV71.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Hung
authors.forename: Hsiang-Ching
authors.initials: HC
authors.lastname: Wang
authors.forename: Shin-Ru
authors.initials: SR
authors.lastname: Shih
authors.forename: I-Fang
authors.initials: IF
authors.lastname: Teng
authors.forename: Ching-Ping
authors.initials: CP
authors.lastname: Tseng
authors.forename: John T-A
authors.initials: JT
authors.lastname: Hsu
mesh_terms: D000465:Algorithms; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002522:Chlorocebus aethiops; D017931:DNA Primers; D015536:Down-Regulation; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D029821:Enterovirus A, Human / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D004769:Enterovirus Infections / Q000188:drug therapy; D006801:Humans; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology*; D010649:Phenylalanine / Q000031:analogs & derivatives; D016133:Polymerase Chain Reaction; D011760:Pyrrolidinones / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D012208:Rhabdomyosarcoma; D014407:Tumor Cells, Cultured; D014633:Valine / Q000031:analogs & derivatives; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D017931:DNA Primers; C494227:IRF9 protein, human; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D007555:Isoxazoles; D011760:Pyrrolidinones; D011994:Recombinant Proteins; D010649:Phenylalanine; D014633:Valine; C118874:rupintrivir