Activity of T-1106 in a Hamster Model of Yellow Fever Virus Infection

Abstract

Yellow fever virus (YFV) causes 30,000 deaths worldwide, despite the availability of a vaccine. There are no approved antiviral therapies for the treatment of YFV disease in humans, and, therefore, these studies were designed to investigate the anti-YFV properties of T-1106, a substituted pyrazine, in a hamster model of YFV disease. Intraperitoneal (i.p.) treatment with 100 mg/kg of body weight/day of T-1106 starting 4 h prior to virus inoculation and continuing twice daily through 7 days post-virus inoculation (dpi) resulted in significantly improved survival, alanine aminotransferase levels in the serum, weight gain, and mean day to death. Virus titer in the liver at 4 dpi was significantly reduced in treated animals, as determined by both quantitative real-time PCR and infectious cell culture assay. No toxicity (weight loss or mortality) was observed at a dose of 100 mg/kg/day in sham-infected control animals. The observed minimal effective dose of T-1106 was 32 mg/kg/day administered either by oral or i.p. treatment. Therapeutic treatment was effective in significantly improving survival when T-1106 was administered beginning as late as 4 days after virus challenge with twice-daily treatment for 8 days at a dose of 100 mg/kg/day. With favorable safety, bioavailability, and postviral challenge treatment efficacy, T-1106 was effective in the treatment of disease in hamsters infected with YFV and should be further studied for potential use as a therapy for human YFV disease.

Activity of T-705 in a Hamster Model of Yellow Fever Virus Infection in Comparison with That of a Chemically Related Compound, T-1106

“…A similar trend in the activities of T-705 and T-1106 was observed against the Jimenez strain of YFV in cell culture (data not shown), suggesting that the activities of T-705 and T-1106 against both virus strains used in this study are similar. Despite the high EC 90 of T-1106 in cell culture, this compound is highly effective in the YFV hamster model, indicating the superior activation of this compound in the animal to that in Vero cells (10). The minimal effective dose for the treatment of influenza virus in a mouse model was sixfold lower than that in the YFV hamster model, indicating that the disparity in the EC 90 s seen in cell culture is not apparent in vivo and may simply be due to different rates of conversion (21).…”

“…The results are given as the relative equivalents, which reflect the amount of YFV RNA present in the sample as extrapolated from a standard curve obtained from amplification of a dilution of total RNA obtained 2 dpi from Vero cells infected with YFV Jimenez. This protocol was previously validated by comparison of the results with those obtained by the infectious cell culture assay (10).…”

“…Serum was collected antemortem from the ocular sinus of all of the animals in each group. ALT (serum glutamic pyruvic transaminase) or AST reagent (Teco Diagnostics, Anaheim, CA) was used, and the protocol was altered for use in 96-well flat-bottomed microplates, as described previously (10). The plate was then read, and the aminotransferase concentrations were determined according to the manufacturer's instructions.…”

“…T-1106, a pyrazine nucleoside analog, was recently shown to significantly improve the rates of survival and disease parameters in hamsters infected with YFV (10). Doses as low as 32 mg/kg of body weight per day (120 mol/kg/day) were effective against the virus.…”

“…injection of hamsters (23). Useful parameters for the evaluation of antiviral compounds include the rate of survival; the YFV titer in the liver; serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels; weight change; and several serum parameters, including elevated bilirubin and blood urea nitrogen levels (10,11,19).…”