title: In vitro and in vivo protection against enterovirus 71 by an antisense phosphorothioate oligonucleotide.
abstract: Enterovirus 71 (EV71) is a highly infectious virus that is a major cause of hand, foot, and mouth disease (HFMD), which can lead to severe neurological complications. Currently, there is no effective therapy against EV71. Five antisense oligodeoxynucleotides targeting the 5'-terminal conserved domain of the viral genome were designed using a method based on multiple predicted target mRNA structures. They were then screened for anti-EV71 activity in vitro based on their ability to inhibit an EV71-induced cytopathic effect (CPE). A novel antisense oligonucleotide (EV5) was tested both in rhabdomyosarcoma (RD) cells and in vivo using a mouse model, with a random oligonucleotide (EV5R) of EV5 as a control. EV5 was identified as having significant anti-EV71 activity in vitro and in vivo without significant cytotoxicity. Treatment of RD and Vero cells with antisense oligodeoxynucleotide EV5 significantly and specifically alleviated the cytopathic effect of EV71 in vitro. The inhibitory effect was dose dependent and specific, with a corresponding decrease in viral RNA and viral protein levels. In vivo, EV5 was specifically effective against EV71 virus in preventing death, decreasing weight reduction and reducing the viral RNA copy number and the level of viral proteins in the lungs, intestines and muscles. These results demonstrate the potential and feasibility of using antisense oligodeoxynucleotides specific for the 5'-terminal conserved domain of the viral genome as an antiviral therapy for EV71 disease.
authors.affiliation: Beijing Institute of Radiation Medicine, Beijing Key Laboratory of New Molecular Diagnosis Technologies for Infectious Diseases, 27 Taiping Road, Haidian District, Beijing, 100850, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhou
authors.forename: Kang
authors.initials: K
authors.lastname: Li
authors.forename: Mingming
authors.initials: M
authors.lastname: Han
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Shengqi
authors.initials: S
authors.lastname: Wang
mesh_terms: D000825:Animal Structures / Q000821:virology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004195:Disease Models, Animal; D029821:Enterovirus A, Human / Q000187:drug effects*; D006232:Hand, Foot and Mouth Disease / Q000517:prevention & control*; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D054735:Phosphorothioate Oligonucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D020319:Oligodeoxyribonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides