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 microg/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/(kgd) 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
Justin G
JG
Institute for Antiviral Research, Department of Animal, Dairy, and Veterinary Sciences, Utah State University, 5600 Old Main Hill, Logan, UT 84322-5600, United States. jgjulander@cc.usu.edu
Bowen
Richard A
RA
Rao
Jagadeeshwar R
JR
Day
Craig
C
Shafer
Kristiina
K
Smee
Donald F
DF
Morrey
John D
JD
Chu
Chung K
CK
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003570:Cytidine Triphosphate / Q000378:metabolism; D004666:Encephalitis Virus, Venezuelan Equine / Q000187:drug effects*; D004685:Encephalomyelitis, Venezuelan Equine / Q000188:drug therapy* / Q000821:virology; D005260:Female; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008813:Mice, Inbred ICR; D014709:Vero Cells
D000998:Antiviral Agents; D003562:Cytidine; D003570:Cytidine Triphosphate; C033357:carbodine