Characterization of pharmacologically active compounds that inhibit poliovirus and enterovirus 71 infectivity.
Poliovirus (PV) and enterovirus 71 (EV71) cause severe neurological symptoms in their infections of the central nervous system. To identify compounds with anti-PV and anti-EV71 activities that would not allow the emergence of resistant mutants, we performed drug screening by utilizing a pharmacologically active compound library targeting cellular factors with PV and EV71 pseudoviruses that encapsidated luciferase-encoding replicons. We have found that metrifudil (N-[2-methylphenyl]methyl)-adenosine) (an A2 adenosine receptor agonist), N(6)-benzyladenosine (an A1 adenosine receptor agonist) and NF449 (4,4',4'',4'''-[carbonylbis[imino-5,1,3-benzenetriyl bis(carbonyl-imino)]] tetrakis (benzene-1,3-disulfonic acid) octasodium salt) (a Gs-alpha inhibitor) have anti-EV71 activity, and that GW5074 (3-(3, 5-dibromo-4-hydroxybenzylidine-5-iodo-1,3-dihydro-indol-2-one)) (a Raf-1 inhibitor) has both anti-PV and anti-EV71 activities. EV71 mutants resistant to metrifudil, N(6)-benzyladenosine and NF449 were isolated after passages in the presence of these compounds, but mutants resistant to GW5074 were not isolated for both PV and EV71. The inhibitory effect of GW5074 was not observed in Sendai virus infection and the treatment did not induce the expression of OAS1 and STAT1 mRNA. Small interfering RNA treatment against putative cellular targets of GW5074, including Raf-1, B-Raf, Pim-1, -2, and -3, HIPK2, GAK, MST2 and ATF-3, did not consistently suppress PV replication. Moreover, downregulation of Raf-1 and B-Raf did not affect the sensitivity of RD cells to the inhibitory effect of GW5074. These results suggest that GW5074 has strong and selective inhibitory effect against the replication of PV and EV71 by inhibiting conserved targets in the infection independently of the interferon response.
Arita
Minetaro
M
Department of Virology II, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan.
Wakita
Takaji
T
Department of Virology II, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan.
Shimizu
Hiroyuki
H
Department of Virology II, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama-shi, Tokyo 208-0011, Japan.
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001557:Benzenesulfonates / Q000737:chemistry / Q000494:pharmacology; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics; D004770:Enterovirus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008826:Microbial Sensitivity Tests / Q000379:methods; D009154:Mutation; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D017955:Poliovirus / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D034622:RNA Interference; D012093:Replicon / Q000187:drug effects / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
C110258:4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate); D000998:Antiviral Agents; D001557:Benzenesulfonates; D036022:Capsid Proteins; D007211:Indoles; D010636:Phenols; C017061:N(6)-benzyladenosine; C082872:metrifudil; D008156:Luciferases; D000241:Adenosine; C489251:5-iodo-3-((3,5-dibromo-4-hydroxyphenyl)methylene)-2-indolinone