Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430

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Abstract
A broad-spectrum antiviral small molecule is reported to act as an inhibitor of viral polymerase activity and is shown to be effective in protecting non-human primates from lethal filovirus infection when administered after exposure. Viruses of the Filoviridae family can cause severe haemorrhagic fever in humans and non-human primates. Mortality rates are extremely high and no vaccines or drugs are currently licensed for the treatment of filovirus diseases. Here Sina Bavari and colleagues report the discovery of a small-molecule viral polymerase inhibitor with in vitro and in vivo antiviral activity against highly pathogenic viruses, including filoviruses such as Ebola virus and Sudan virus. The compound, BCX4430, is an adenosine analogue that acts as a non-obligate chain terminator. Administered either orally or intramuscularly, it can completely protect cynomolgus macaques from Marburg virus, even when administered as late as 48 hours after infection. 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.