Mutation in enterovirus 71 capsid protein VP1 confers resistance to the inhibitory effects of pyridyl imidazolidinone.
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.
Shih
Shin-Ru
SR
School of Medical Technology, Chang Gung University, 259 Wen-Hua First Rd., Kwei-Shan, Tao-Yuan, Taiwan. srshih@mail.cgu.edu.tw
Tsai
Mun-Chung
MC
Tseng
Sung-Nien
SN
Won
Kuo-Fang
KF
Shia
Kak-Shan
KS
Li
Wen-Tai
WT
Chern
Jyh-Haur
JH
Chen
Guang-Wu
GW
Lee
Chung-Chi
CC
Lee
Yen-Chun
YC
Peng
Kuan-Chang
KC
Chao
Yu-Sheng
YS
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D036022:Capsid Proteins / Q000235:genetics*; D002522:Chlorocebus aethiops; D018076:DNA, Complementary / Q000235:genetics; D015195:Drug Design; D024882:Drug Resistance, Viral; D004770:Enterovirus / Q000187:drug effects* / Q000235:genetics*; D007093:Imidazoles / Q000494:pharmacology*; D007700:Kinetics; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011725:Pyridines / Q000494:pharmacology*; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D014709:Vero Cells; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D036022:Capsid Proteins; D018076:DNA, Complementary; D007093:Imidazoles; D011725:Pyridines; D012367:RNA, Viral; C492441:1-(5-(4-bromophenoxy)pentyl)-3-(4-pyridyl)-2-imidazolidinone