BCX4430, a novel nucleoside analog, effectively treats yellow fever in a Hamster model.

Abstract

No effective antiviral therapies are currently available to treat disease after infection with yellow fever virus (YFV). A Syrian golden hamster model of yellow fever (YF) was used to characterize the effect of treatment with BCX4430, a novel adenosine nucleoside analog. Significant improvement in survival was observed after treatment with BCX4430 at 4 mg/kg of body weight per day dosed intraperitoneally (i.p.) twice daily (BID). Treatment with BCX4430 at 12.5 mg/kg/day administered i.p. BID for 7 days offered complete protection from mortality and also resulted in significant improvement of other YF disease parameters, including weight loss, serum alanine aminotransferase levels (6 days postinfection [dpi]), and viremia (4 dpi). In uninfected hamsters, BCX4430 at 200 mg/kg/day administered i.p. BID for 7 days was well tolerated and did not result in mortality or weight loss, suggesting a potentially wide therapeutic index. Treatment with BCX4430 at 12 mg/kg/day i.p. remained effective when administered once daily and for only 4 days. Moreover, BCX4430 dosed at 200 mg/kg/day i.p. BID for 7 days effectively treated YF, even when treatment was delayed up to 4 days after virus challenge, corresponding with peak viral titers in the liver and serum. BCX4430 treatment did not preclude a protective antibody response, as higher neutralizing antibody (nAb) concentrations corresponded with increasing delays of treatment initiation, and greater nAb responses resulted in the protection of animals from a secondary challenge with YFV. In summary, BCX4430 is highly active in a hamster model of YF, even when treatment is initiated at the peak of viral replication.

• Authors: Justin G Julander, Shanta Bantia, Brian R Taubenheim, Dena M Minning, Pravin Kotian, John D Morrey, Donald F Smee, William P Sheridan, Yarlagadda S Babu
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 58 Issue 11 Pg. 6607-14 (Nov 2014) ISSN: 1098-6596 [Electronic] United States
• PMID: 25155605 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Chemical References

• Antibodies, Neutralizing
• Antibodies, Viral
• Antiviral Agents
• Purine Nucleosides
• Pyrrolidines
• Alanine Transaminase
• Adenine
• Adenosine
• galidesivir

Topics

• Adenine (analogs & derivatives)
• Adenosine (analogs & derivatives, therapeutic use)
• Alanine Transaminase (blood)
• Animals
• Antibodies, Neutralizing (blood)
• Antibodies, Viral (blood)
• Antiviral Agents (therapeutic use)
• Cells, Cultured
• Cricetinae
• Disease Models, Animal
• Female
• Mesocricetus
• Purine Nucleosides (therapeutic use)
• Pyrrolidines
• Treatment Outcome
• Viral Plaque Assay
• Viremia (drug therapy, virology)
• Yellow Fever (drug therapy, mortality, virology)
• Yellow fever virus (drug effects, immunology)