title: The multi-targeted kinase inhibitor sorafenib inhibits enterovirus 71 replication by regulating IRES-dependent translation of viral proteins.
abstract: The activation of ERK and p38 signal cascade in host cells has been demonstrated to be essential for picornavirus enterovirus 71 (EV71) replication and up-regulation of virus-induced cyclooxygenase-2 (COX-2)/prostaglandins E2 (PGE2) expression. The aim of this study was to examine the effects of sorafenib, a clinically approved anti-cancer multi-targeted kinase inhibitor, on the propagation and pathogenesis of EV71, with a view to its possible mechanism and potential use in the design of therapy regimes for Hand foot and mouth disease (HFMD) patients with life threatening neurological complications. In this study, non-toxic concentrations of sorafenib were shown to inhibit the yield of infectious progeny EV71 (clinical BC08 strain) by about 90% in three different cell types. A similar inhibitory effect of sorafenib was observed on the synthesis of both viral genomic RNA and the VP1 protein. Interestingly, sorafenib exerted obvious inhibition of the EV71 internal ribosomal entry site (IRES)-mediated translation, the first step in picornavirus replication, by linking it to a firefly luciferase reporter gene. Sorafenib was also able to prevent both EV71-induced CPE and the activation of ERK and p38, which contributes to up-regulation COX-2/PGE2 expression induced by the virus. Overall, this study shows that sorafenib strongly inhibits EV71 replication at least in part by regulating viral IRES-dependent translation of viral proteins, indicating a novel potential strategy for the treatment of HFMD patients with severe neurological complications. To our knowledge, this is the first report that investigates the mechanism by which sorafenib inhibits EV71 replication.
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Duan
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China.
authors.forename: Jitao
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China.
authors.forename: Zhenlong
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: School of Health Sciences, Macao Polytechnic Institute, Macao SAR 999078, People's Republic of China.
authors.forename: Lirong
authors.initials: L
authors.lastname: Meng
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, People's Republic of China. Electronic address: ypeng78@bjmu.edu.cn.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Peng
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D029821:Enterovirus A, Human / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D000077157:Sorafenib; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D014764:Viral Proteins; D009536:Niacinamide; D000077157:Sorafenib
keywords: Antiviral therapy; EV71; IRES; Sorafenib