Novel antiviral agent DTriP-22 targets RNA-dependent RNA polymerase of enterovirus 71.
Enterovirus 71 (EV71) has emerged as an important virulent neurotropic enterovirus in young children. DTriP-22 (4{4-[(2-bromo-phenyl)-(3-methyl-thiophen-2-yl)-methyl]-piperazin-1-yl}-1-pheny-1H-pyrazolo[3,4-d]pyrimidine) was found to be a novel and potent inhibitor of EV71. The molecular target of this compound was identified by analyzing DTriP-22-resistant viruses. A substitution of lysine for Arg163 in EV71 3D polymerase rendered the virus drug resistant. DTriP-22 exhibited the ability to inhibit viral replication by reducing viral RNA accumulation. The compound suppressed the accumulated levels of both positive- and negative-stranded viral RNA during virus infection. An in vitro polymerase assay indicated that DTriP-22 inhibited the poly(U) elongation activity, but not the VPg uridylylation activity, of EV71 polymerase. These findings demonstrate that the nonnucleoside analogue DTriP-22 acts as a novel inhibitor of EV71 polymerase. DTriP-22 also exhibited a broad spectrum of antiviral activity against other picornaviruses, which highlights its potential in the development of antiviral agents.
Chen
Tzu-Chun
TC
Department of Medical Biotechnology and Laboratory Science, Chang Gung University, 259 Wen-Hua 1st Rd., Kwei-Shan, Taoyuan, Taiwan.
Chang
Hwan-You
HY
Lin
Pei-Fen
PF
Chern
Jyh-Haur
JH
Hsu
John Tsu-An
JT
Chang
Chu-Yi
CY
Shih
Shin-Ru
SR
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004285:Dogs; D004770:Enterovirus / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D004769:Enterovirus Infections / Q000188:drug therapy; D006367:HeLa Cells; D006801:Humans; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014709:Vero Cells
D000998:Antiviral Agents; D011994:Recombinant Proteins; D012324:RNA-Dependent RNA Polymerase