title: Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430.
abstract: Filoviruses are emerging pathogens and causative agents of viral haemorrhagic fever. Case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, exceeding 90% (ref. 1). Licensed therapeutic or vaccine products are not available to treat filovirus diseases. Candidate therapeutics previously shown to be efficacious in non-human primate disease models are based on virus-specific designs and have limited broad-spectrum antiviral potential. Here we show that BCX4430, a novel synthetic adenosine analogue, inhibits infection of distinct filoviruses in human cells. Biochemical, reporter-based and primer-extension assays indicate that BCX4430 inhibits viral RNA polymerase function, acting as a non-obligate RNA chain terminator. Post-exposure intramuscular administration of BCX4430 protects against Ebola virus and Marburg virus disease in rodent models. Most importantly, BCX4430 completely protects cynomolgus macaques from Marburg virus infection when administered as late as 48 hours after infection. In addition, BCX4430 exhibits broad-spectrum antiviral activity against numerous viruses, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses and flaviviruses. This is the first report, to our knowledge, of non-human primate protection from filovirus disease by a synthetic drug-like small molecule. We provide additional pharmacological characterizations supporting the potential development of BCX4430 as a countermeasure against human filovirus diseases and other viral diseases representing major public health threats.
authors.affiliation: Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA.
authors.forename: Travis K
authors.initials: TK
authors.lastname: Warren
authors.affiliation: Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Wells
authors.affiliation: Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA.
authors.forename: Rekha G
authors.initials: RG
authors.lastname: Panchal
authors.affiliation: Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Stuthman
authors.affiliation: Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Garza
authors.affiliation: Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA.
authors.forename: Sean A
authors.initials: SA
authors.lastname: Van Tongeren
authors.affiliation: Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA.
authors.forename: Lian
authors.initials: L
authors.lastname: Dong
authors.affiliation: Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA.
authors.forename: Cary J
authors.initials: CJ
authors.lastname: Retterer
authors.affiliation: Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA.
authors.forename: Brett P
authors.initials: BP
authors.lastname: Eaton
authors.affiliation: Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Pegoraro
authors.affiliation: Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA.
authors.forename: Shelley
authors.initials: S
authors.lastname: Honnold
authors.affiliation: BioCryst Pharmaceuticals Inc., Durham, North Carolina 27703, USA.
authors.forename: Shanta
authors.initials: S
authors.lastname: Bantia
authors.affiliation: BioCryst Pharmaceuticals Inc., Durham, North Carolina 27703, USA.
authors.forename: Pravin
authors.initials: P
authors.lastname: Kotian
authors.affiliation: BioCryst Pharmaceuticals Inc., Durham, North Carolina 27703, USA.
authors.forename: Xilin
authors.initials: X
authors.lastname: Chen
authors.affiliation: 1] BioCryst Pharmaceuticals Inc., Durham, North Carolina 27703, USA [2] Wilco Consulting, LLC, Durham, North Carolina 27712, USA.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Taubenheim
authors.affiliation: Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA.
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Welch
authors.affiliation: MedExpert Consulting, Inc., Indialantic, Florida 32903, USA.
authors.forename: Dena M
authors.initials: DM
authors.lastname: Minning
authors.affiliation: BioCryst Pharmaceuticals Inc., Durham, North Carolina 27703, USA.
authors.forename: Yarlagadda S
authors.initials: YS
authors.lastname: Babu
authors.affiliation: BioCryst Pharmaceuticals Inc., Durham, North Carolina 27703, USA.
authors.forename: William P
authors.initials: WP
authors.lastname: Sheridan
authors.affiliation: Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA.
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000241:Adenosine / Q000031:analogs & derivatives*; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D029043:Ebolavirus / Q000187:drug effects; D016563:Filoviridae / Q000187:drug effects* / Q000201:enzymology; D018702:Filoviridae Infections / Q000517:prevention & control* / Q000821:virology*; D019142:Hemorrhagic Fever, Ebola / Q000517:prevention & control / Q000821:virology; D006801:Humans; D007273:Injections, Intramuscular; D008252:Macaca fascicularis / Q000821:virology; D008379:Marburg Virus Disease / Q000517:prevention & control / Q000821:virology; D029024:Marburgvirus / Q000187:drug effects; D011684:Purine Nucleosides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011759:Pyrrolidines; D012313:RNA / Q000096:biosynthesis; D013997:Time Factors
chemical_list: D000998:Antiviral Agents; D011684:Purine Nucleosides; D011759:Pyrrolidines; D012313:RNA; D012321:DNA-Directed RNA Polymerases; D000225:Adenine; D000241:Adenosine; C517546:galidesivir