Treatment of Venezuelan Equine Encephalitis Virus Infection with (-)-Carbodine
Venezuelan equine encephalitis virus (VEEV) may cause encephalitis in humans, for which no FDA-approved antiviral treatment is available. Carbocyclic cytosine (carbodine) has broad-spectrum activity but toxicity has limited its utility. It was anticipated that one of the enantiomers of carbodine would show enhanced activity and reduced toxicity. The activity of the d-(−) enantiomer of carbodine [(−)-carbodine] was evaluated by infectious cell culture assay and was found to have a 50% effective concentration (EC50) of 0.2 μg/ml against the TC-83 vaccine strain of VEEV in Vero cells, while the l-(+) enantiomer had no activity. Virus titer inhibition correlated with intracellular cytidine triphosphate reduction after treatment with (−)-carbodine, as determined by HPLC analysis. Pre-treatment with 200 mg/(kg d) resulted in significant improvement in survival, virus load in the brain, weight change, and mean day-to-death in a mouse model of TC-83 VEEV disease. A single dose of (−)-carbodine resulted in a slight extension of mean time to death in mice infected with wild-type VEEV. Post-virus exposure treatment with (−)-carbodine was effective in significantly improving disease parameters in mice infected with TC-83 VEEV when treatment was initiated as late as 4 days post-virus installation (dpi). It is remarkable that (−)-carbodine is effective when initiated after the establishment of brain infection.
Julander J.G., Bowen R.A., Rao J.R., Day C.D., Shafer K., Smee D.F., Morrey J.D., Chu C.K. 2008. Treatment of Venezuelan equine encephalitis virus infection with (-)-carbodine. Antiviral Research 80(3): 309-315.