title: 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.affiliation: Institute for Antiviral Research, Utah State University, Logan, Utah, USA justin.julander@usu.edu.
authors.forename: Justin G
authors.initials: JG
authors.lastname: Julander
authors.affiliation: BioCryst Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: Shanta
authors.initials: S
authors.lastname: Bantia
authors.affiliation: BioCryst Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Taubenheim
authors.affiliation: MedExpert Consulting, Inc., Indialantic, Florida, USA.
authors.forename: Dena M
authors.initials: DM
authors.lastname: Minning
authors.affiliation: BioCryst Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: Pravin
authors.initials: P
authors.lastname: Kotian
authors.affiliation: Institute for Antiviral Research, Utah State University, Logan, Utah, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Morrey
authors.affiliation: Institute for Antiviral Research, Utah State University, Logan, Utah, USA.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Smee
authors.affiliation: BioCryst Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Sheridan
authors.affiliation: BioCryst Pharmaceuticals, Inc., Durham, North Carolina, USA.
authors.forename: Yarlagadda S
authors.initials: YS
authors.lastname: Babu
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000241:Adenosine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D000998:Antiviral Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D006224:Cricetinae; D004195:Disease Models, Animal; D005260:Female; D008647:Mesocricetus; D011684:Purine Nucleosides / Q000627:therapeutic use*; D011759:Pyrrolidines; D016896:Treatment Outcome; D010948:Viral Plaque Assay; D014766:Viremia / Q000188:drug therapy / Q000821:virology; D015004:Yellow Fever / Q000188:drug therapy* / Q000401:mortality / Q000821:virology; D015005:Yellow fever virus / Q000187:drug effects* / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000998:Antiviral Agents; D011684:Purine Nucleosides; D011759:Pyrrolidines; D000410:Alanine Transaminase; D000225:Adenine; D000241:Adenosine; C517546:galidesivir