title: Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model.
abstract: Zika virus (ZIKV) is currently undergoing pandemic emergence. While disease is typically subclinical, severe neurologic manifestations in fetuses and newborns after congenital infection underscore an urgent need for antiviral interventions. The adenosine analog BCX4430 has broad-spectrum activity against a wide range of RNA viruses, including potent in vivo activity against yellow fever, Marburg and Ebola viruses. We tested this compound against African and Asian lineage ZIKV in cytopathic effect inhibition and virus yield reduction assays in various cell lines. To further evaluate the efficacy in a relevant animal model, we developed a mouse model of severe ZIKV infection, which recapitulates various human disease manifestations including peripheral virus replication, conjunctivitis, encephalitis and myelitis. Time-course quantification of viral RNA accumulation demonstrated robust viral replication in several relevant tissues, including high and persistent viral loads observed in the brain and testis. The presence of viral RNA in various tissues was confirmed by an infectious culture assay as well as immunohistochemical staining of tissue sections. Treatment of ZIKV-infected mice with BCX4430 significantly improved outcome even when treatment was initiated during the peak of viremia. The demonstration of potent activity of BCX4430 against ZIKV in a lethal mouse model warrant its continued clinical development.
authors.affiliation: Institute for Antiviral Research, Utah State University, Logan, UT, USA. Electronic address: justin.julander@usu.edu.
authors.forename: Justin G
authors.initials: JG
authors.lastname: Julander
authors.affiliation: Institute for Antiviral Research, Utah State University, Logan, UT, USA.
authors.forename: Venkatraman
authors.initials: V
authors.lastname: Siddharthan
authors.affiliation: Institute for Antiviral Research, Utah State University, Logan, UT, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Evans
authors.affiliation: BioCryst Pharmaceuticals Inc., Durham, NC, USA.
authors.forename: Ray
authors.initials: R
authors.lastname: Taylor
authors.affiliation: Institute for Antiviral Research, Utah State University, Logan, UT, USA.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Tolbert
authors.affiliation: Co-Diagnostics Inc., Bountiful, UT, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Apuli
authors.affiliation: Institute for Antiviral Research, Utah State University, Logan, UT, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Stewart
authors.affiliation: Institute for Antiviral Research, Utah State University, Logan, UT, USA.
authors.forename: Preston
authors.initials: P
authors.lastname: Collins
authors.affiliation: Institute for Antiviral Research, Utah State University, Logan, UT, USA.
authors.forename: Makda
authors.initials: M
authors.lastname: Gebre
authors.affiliation: Institute for Antiviral Research, Utah State University, Logan, UT, USA.
authors.forename: Skot
authors.initials: S
authors.lastname: Neilson
authors.affiliation: Department of Animal Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Van Wettere
authors.affiliation: Department of Animal Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
authors.forename: Young-Min
authors.initials: YM
authors.lastname: Lee
authors.affiliation: BioCryst Pharmaceuticals Inc., Durham, NC, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Sheridan
authors.affiliation: Institute for Antiviral Research, Utah State University, Logan, UT, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Morrey
authors.affiliation: BioCryst Pharmaceuticals Inc., Durham, NC, USA.
authors.forename: Y S
authors.initials: YS
authors.lastname: Babu
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000241:Adenosine / Q000031:analogs & derivatives; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D001921:Brain / Q000821:virology; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D011684:Purine Nucleosides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D011759:Pyrrolidines; D012367:RNA, Viral; D013737:Testis / Q000821:virology; D019562:Viral Load / Q000187:drug effects; D014766:Viremia; D014779:Virus Replication / Q000187:drug effects; D000071244:Zika Virus / Q000187:drug effects*; D000071243:Zika Virus Infection / Q000188:drug therapy* / Q000821:virology
chemical_list: D000998:Antiviral Agents; D011684:Purine Nucleosides; D011759:Pyrrolidines; D012367:RNA, Viral; D000225:Adenine; D000241:Adenosine; C517546:galidesivir
keywords: AG129 mice; Antiviral; BCX4430; Flavivirus; Ribavirin; ZIKV; Zika virus