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Published on: October 11, 2013
Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430
Travis K Warren1, Jay Wells1, Rekha G Panchal1
1Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA.
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.
Insights
A novel synthetic adenosine analogue, BCX4430, shows promise as a broad-spectrum antiviral. It effectively inhibits filoviruses like Ebola and Marburg, offering protection even after exposure in animal models.
Area of Science:
- Virology
- Infectious Diseases
- Drug Discovery
Background:
- Filoviruses, such as Ebola and Marburg, are highly lethal emerging pathogens causing viral hemorrhagic fever.
- Current treatments and vaccines for filovirus diseases are limited, with high case fatality rates.
- Existing candidate therapeutics are often virus-specific, lacking broad-spectrum antiviral potential.
Purpose of the Study:
- To evaluate the antiviral activity of BCX4430, a novel synthetic adenosine analogue, against filoviruses.
- To determine the mechanism of action and in vivo efficacy of BCX4430 in relevant disease models.
- To assess the broad-spectrum antiviral potential of BCX4430 against other viral families.
Main Methods:
- Biochemical assays, reporter-based assays, and primer-extension assays were used to investigate the mechanism of action.
- In vivo efficacy studies were conducted in rodent models for Ebola virus and Marburg virus disease.
- Cynomolgus macaques were used to assess protection against Marburg virus infection post-exposure.
Main Results:
- BCX4430 demonstrated inhibition of distinct filoviruses in human cells by targeting viral RNA polymerase as a non-obligate RNA chain terminator.
- Intramuscular administration of BCX4430 protected against Ebola and Marburg virus disease in rodent models.
- Complete protection was observed in cynomolgus macaques infected with Marburg virus when BCX4430 was administered up to 48 hours post-infection.
- BCX4430 exhibited broad-spectrum antiviral activity against bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses, and flaviviruses.
Conclusions:
- BCX4430 is a potent inhibitor of filovirus replication with a novel mechanism of action.
- This study presents the first report of a synthetic small molecule protecting non-human primates from filovirus disease.
- BCX4430 shows significant potential as a broad-spectrum antiviral therapeutic for filovirus diseases and other viral threats.
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