TABLE 2.

Resistance pattern of recombinant CVB3 carrying 2C mutations A224V, I227V, and A229V and cross-resistance pattern with other antienterovirus compoundsa

Clone2C mutationbMean EC50 (μM) of indicated antiviral molecule ± SDc
A224VI227VA229V2C inhibitorsNon-2C inhibitors
TBZE-029HBBMRL-1237GuanidineEnviroximeRuprintrivir
WTd7.2 ± 3.155 ± 215 ± 6272 ± 50.18 ± 0.034.7 ± 1.0
1X9.3 ± 0.956 ± 412 ± 21,681 ± 150.18 ± 0.034.4 ± 0.5
2X10 ± 059 ± 3199 ± 27286 ± 190.22 ± 0.024.3 ± 0.4
3XDepDepDepDep
4XX>330283 ± 18>3141,687 ± 600.17 ± 0.054.4 ± 0.4
5XXDepDepDepDep
6XX210 ± 72270 ± 23>3141,657 ± 600.14 ± 0.014.3 ± 0.6
7XXX>330>446>314>10,4680.20 ± 0.012.4 ± 1.5
Res poole>330>446202 ± 12>10,4680.47 ± 0.174.3 ± 0.9
  • a Mutations at residues 224, 227, and 229 in protein 2C were introduced, either alone or combined, in a full-length cDNA of CVB3. In vitro transcription, followed by transfection, led to seven recombinant viruses that were evaluated for their susceptibility to TBZE-029 and reference compounds.

  • b X indicates the presence of the mutation.

  • c Data were determined by inhibition of CPE formation. Dep, clones that were dependent on GuaHCl in order to generate infectious virus upon transfection. Data are from at least three independent experiments. Boldface indicates resistance to the tested drug.

  • d WT, wild type.

  • e Res pool, resistant pool of CVB3, obtained after serial passaging in the presence of TBZE-029 and prior to plaque purification.