Treatment of Venezuelan equine encephalitis virus infection with (−)-carbodine

• Published in: Antiviral research Vol. 80; no. 3; pp. 309 - 315
• Main Authors: Julander, Justin G., Bowen, Richard A., Rao, Jagadeeshwar R., Day, Craig, Shafer, Kristiina, Smee, Donald F., Morrey, John D., Chu, Chung K.
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.12.2008; Elsevier
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral; Antiviral agents; Antiviral Agents - pharmacology; Arboviral encephalitis; Arboviroses; Biological and medical sciences; C3H/HeN mouse; Carbodine; Cercopithecus aethiops; Cytidine - analogs & derivatives; Cytidine - pharmacology; Cytidine Triphosphate - metabolism; Encephalitis Virus, Venezuelan Equine - drug effects; Encephalomyelitis, Venezuelan Equine - drug therapy; Encephalomyelitis, Venezuelan Equine - virology; Female; Human viral diseases; Humans; Infectious diseases; Medical sciences; Mice; Mice, Inbred C3H; Mice, Inbred ICR; Miscellaneous; Pharmacology. Drug treatments; TC-83; Tropical viral diseases; Venezuelan equine encephalitis; Venezuelan equine encephalitis virus; Vero Cells; Viral diseases; Virus; Virus; C3H/HeN mouse; Antiviral; Carbodine; Venezuelan equine encephalitis; TC-83; Venezuelan equine encephalomyelitis; Venezuelan equine encephalomyelitis virus; Togaviridae; Carbanucleoside; Enantiomer; Arbovirus disease; Cytosine; Nervous system diseases; Rodentia; Cerebral disorder; Infection; Vertebrata; Mammalia; Treatment; Mouse; Viral disease; Animal; Central nervous system disease; Alphavirus; Veterinary
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2008.07.002

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 (EC 50) 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.