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Antimicrobial Agents and Chemotherapy, July 2009, p. 2740-2747, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00101-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Novel Antiviral Agent DTriP-22 Targets RNA-Dependent RNA Polymerase of Enterovirus 71{triangledown}

Tzu-Chun Chen,1,2,5 Hwan-You Chang,5 Pei-Fen Lin,2 Jyh-Haur Chern,4 John Tsu-An Hsu,4 Chu-Yi Chang,6 and Shin-Ru Shih1,2,3,4*

Research Center for Emerging Viral Infections, Chang Gung University, Taoyuan, Taiwan,1 Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, Taiwan,2 Clinical Virology Laboratory, Chang Gung Memorial Hospital, Taoyuan, Taiwan,3 Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Chunan, Taiwan,4 Institute of Molecular Medicine, National Tsing Hua University, Hsinchu, Taiwan,5 Department of Computer Science and Information Engineering, Chang Gung University, Taoyuan, Taiwan6

Received 23 January 2009/ Returned for modification 17 March 2009/ Accepted 28 April 2009

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.

* Corresponding author. Mailing address: Department of Medical Biotechnology and Laboratory Science, Chang Gung University, 259 Wen-Hua 1st Rd., Kwei-Shan, Taoyuan 333, Taiwan. Phone: 886-3-2118800, ext. 5497. Fax: 886-3-2118174. E-mail: srshih{at}mail.cgu.edu.tw

{triangledown} Published ahead of print on 4 May 2009.

Antimicrobial Agents and Chemotherapy, July 2009, p. 2740-2747, Vol. 53, No. 7
0066-4804/09/$08.00+0     doi:10.1128/AAC.00101-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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