Characterization of poliovirus variants selected for resistance to the antiviral compound V-073.
V-073, a small-molecule capsid inhibitor originally developed for nonpolio enterovirus indications is considerably more potent against polioviruses. All poliovirus isolates tested to date (n = 45), including wild, vaccine, vaccine-derived, and laboratory strains, are susceptible to the antiviral capsid inhibitor V-073. We grew poliovirus in the presence of V-073 to allow for the identification of variants with reduced susceptibility to the drug. Sequence analysis of 160 independent resistant variants (80 isolates of poliovirus type 1, 40 isolates each of types 2 and 3) established that V-073 resistance involved a single amino acid change in either of two virus capsid proteins, VP1 (67 of 160 [42%]) or VP3 (93 of 160 [58%]). In resistant variants with a VP1 change, the majority (53 of 67 [79%]) exhibited a substitution of isoleucine at position 194 (equivalent position 192 in type 3) with either methionine or phenylalanine. Of those with a VP3 change, alanine at position 24 was replaced with valine in all variants (n = 93). The resistance phenotype was relatively stable upon passage of viruses in cell culture in the absence of drug. Single-step growth studies showed no substantial differences between drug-resistant variants and the virus stocks from which they were derived, while the resistant viruses were generally more thermally labile than the corresponding drug-susceptible parental viruses. These studies provide a foundation from which to build a greater understanding of resistance to antiviral compound V-073.
Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Hong-Mei
HM
Liu
Jason A
JA
Roberts
Deborah
D
Moore
Barbara
B
Anderson
Mark A
MA
Pallansch
Daniel C
DC
Pevear
Marc S
MS
Collett
M Steven
MS
Oberste
D019943:Amino Acid Substitution; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002213:Capsid / Q000737:chemistry; D036022:Capsid Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics; D055768:Halogenated Diphenyl Ethers / Q000494:pharmacology*; D006801:Humans; D008253:Macaca mulatta; D009154:Mutation; D010647:Phenyl Ethers; D017955:Poliovirus / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D010948:Viral Plaque Assay
D000596:Amino Acids; D000998:Antiviral Agents; D036022:Capsid Proteins; D055768:Halogenated Diphenyl Ethers; D010647:Phenyl Ethers; C442540:VP1 protein, Poliovirus; C442542:VP3 protein, Poliovirus; C000619933:pocapavir