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Antimicrobial Agents and Chemotherapy, September 2004, p. 3523-3529, Vol. 48, No. 9
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.9.3523-3529.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mutation in Enterovirus 71 Capsid Protein VP1 Confers Resistance to the Inhibitory Effects of Pyridyl Imidazolidinone

Shin-Ru Shih,1* Mun-Chung Tsai,1 Sung-Nien Tseng,1 Kuo-Fang Won,1 Kak-Shan Shia,2 Wen-Tai Li,2 Jyh-Haur Chern,2 Guang-Wu Chen,3 Chung-Chi Lee,2 Yen-Chun Lee,2 Kuan-Chang Peng,2 and Yu-Sheng Chao2

School of Medical Technology, Chang Gung University, Taoyuan,1 Division of Biotechnology and Pharmaceutical Research,2 Division of Biostatistics and Bioinformatics, National Health Research Institutes, Taipei, Taiwan3

Received 4 November 2003/ Returned for modification 5 February 2004/ Accepted 10 May 2004

Enterovirus 71 is one of the most important pathogens in the family of Picornaviridae that can cause severe complications in the postpoliovirus era, such as encephalitis, pulmonary edema, and even death. Pyridyl imidazolidinone is a novel class of potent and selective human enterovirus 71 inhibitor. Pyridyl imidazolidinone was identified by using computer-assisted drug design. This virologic investigation demonstrates that BPR0Z-194, one of the pyridyl imidazolidinones, targets enterovirus 71 capsid protein VP1. Time course experiments revealed that BPR0Z-194 effectively inhibited virus replication in the early stages, implying that the compound can inhibit viral adsorption and/or viral RNA uncoating. BPR0Z-194 was used to select and characterize the drug-resistant viruses. Sequence analysis of the VP1 region showed that the resistant variants differed consistently by seven amino acids in VP1 region from their parental drug-sensitive strains. Site-directed mutagenesis of enterovirus 71 infectious cDNA revealed that a single amino acid alteration at the position 192 of VP1 can confer resistance to the inhibitory effects of BPR0Z-194.

* Corresponding author. Mailing address: School of Medical Technology, Chang Gung University, 259 Wen-Hua First Rd., Kwei-Shan, Tao-Yuan, Taiwan. Phone: 886-3-2118800, ext. 5497. Fax: 886-3-2118174. E-mail: srshih{at}mail.cgu.edu.tw.

Antimicrobial Agents and Chemotherapy, September 2004, p. 3523-3529, Vol. 48, No. 9
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.9.3523-3529.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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