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: Travis K Warren, Jay Wells, Rekha G Panchal, Kelly S Stuthman, Nicole L Garza, Sean A Van Tongeren, Lian Dong, Cary J Retterer, Brett P Eaton, Gianluca Pegoraro, Shelley Honnold, Shanta Bantia, Pravin Kotian, Xilin Chen, Brian R Taubenheim, Lisa S Welch, Dena M Minning, Yarlagadda S Babu, William P Sheridan, Sina Bavari
• Journal: Nature (Nature) Vol. 508 Issue 7496 Pg. 402-5 (Apr 17 2014) ISSN: 1476-4687 [Electronic] England
• PMID: 24590073 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antiviral Agents
• Purine Nucleosides
• Pyrrolidines
• RNA
• DNA-Directed RNA Polymerases
• Adenine
• Adenosine
• galidesivir

Topics

• Adenine (analogs & derivatives)
• Adenosine (analogs & derivatives)
• Administration, Oral
• Animals
• Antiviral Agents (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• DNA-Directed RNA Polymerases (antagonists & inhibitors, metabolism)
• Disease Models, Animal
• Ebolavirus (drug effects)
• Filoviridae (drug effects, enzymology)
• Filoviridae Infections (prevention & control, virology)
• Hemorrhagic Fever, Ebola (prevention & control, virology)
• Humans
• Injections, Intramuscular
• Macaca fascicularis (virology)
• Marburg Virus Disease (prevention & control, virology)
• Marburgvirus (drug effects)
• Purine Nucleosides (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Pyrrolidines
• RNA (biosynthesis)
• Time Factors