Giuseppe
Emeritus
[Source: Nature, full page: (LINK). Abstract, edited.]
Nature | Letter
Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430
Travis K. Warren,<SUP>1</SUP><SUP>, </SUP>Jay Wells,<SUP>1</SUP><SUP>, </SUP>Rekha G. Panchal,<SUP>1</SUP><SUP>, </SUP>Kelly S. Stuthman,<SUP>1</SUP><SUP>, </SUP>Nicole L. Garza,<SUP>1</SUP><SUP>, </SUP>Sean A. Van Tongeren,<SUP>1</SUP><SUP>, </SUP>Lian Dong,<SUP>1</SUP><SUP>, </SUP>Cary J. Retterer,<SUP>1</SUP><SUP>, </SUP>Brett P. Eaton,<SUP>1</SUP><SUP>, </SUP>Gianluca Pegoraro,<SUP>1</SUP><SUP>, </SUP>Shelley Honnold,<SUP>1</SUP><SUP>, </SUP>Shanta Bantia,<SUP>2</SUP><SUP>, </SUP>Pravin Kotian,<SUP>2</SUP><SUP>, </SUP>Xilin Chen,<SUP>2</SUP><SUP>, </SUP>Brian R. Taubenheim,<SUP>2, 4</SUP><SUP>, </SUP>Lisa S. Welch,<SUP>1</SUP><SUP>, </SUP>Dena M. Minning,<SUP>3</SUP><SUP>, </SUP>Yarlagadda S. Babu,<SUP>2</SUP><SUP>, </SUP>William P. Sheridan<SUP>2</SUP><SUP>, </SUP>& Sina Bavari<SUP>1</SUP>
<SUP></SUP>
Journal name: Nature - Volume: 508, Pages: 402?405 - Date published: (17 April 2014) - DOI: doi:10.1038/nature13027
Received 02 December 2012 - Accepted 13 January 2014 - Published online 02 March 2014
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.
Subject terms
harmaceutics?Antivirals?Marburg virus?Ebola virus
Affiliations
1) Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA: 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, Lisa S. Welch & Sina Bavari
2) BioCryst Pharmaceuticals Inc., Durham, North Carolina 27703, USA: Shanta Bantia, Pravin Kotian, Xilin Chen, Brian R. Taubenheim, Yarlagadda S. Babu & William P. Sheridan
3) MedExpert Consulting, Inc., Indialantic, Florida 32903, USA: Dena M. Minning
Present address: Wilco Consulting, LLC, Durham, North Carolina 27712, USA.
Contributions
Y.S.B. and P.K. were responsible for the synthesis of BCX4430 and other small molecules. T.K.W. designed and supervised activities associated with rodent and non-human primate efficacy evaluations, evaluated study results, and wrote the manuscript. J.W., K.S.D., N.L.G. and S.A.V.T. conducted the rodent and non-human primate efficacy studies and performed sample analyses. R.G.P., G.P., C.J.R. and B.P.E. designed and executed cell-based filovirus assays and analysed these data. S. Bantia, Y.S.B., D.M.M., W.P.S., B.R.T. and others designed and analysed data from cell-based antiviral assays. L.D. conducted quantitative PCR analysis. B.R.T. conducted statistical evaluations of in vivo study results. S.H. performed post-mortem analysis of all non-human primate subjects. Y.S.B. supervised the pharmacokinetics studies of BCX4430 and W.P.S. conducted pharmacokinetics data analysis. S. Bantia conducted assessments of BCX4430 metabolite analysis and incorporation into host nucleic acids. X.C. conducted chain termination experiments. T.K.W., D.M.M., L.S.W., B.R.T., Y.S.B., W.P.S. and S. Bavari designed experiments, evaluated results and provided project oversight.
Competing financial interests
S. Bantia, P.K., Y.S.B. and BioCryst Pharmaceuticals, Inc. claim intellectual property regarding BCX4430 for treatment of viral infections. S. Bantia, X.C., P.K., Y.S.B. and W.P.S. are employees of BioCryst Pharmaceuticals, Inc.
-
-------
Nature | Letter
Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430
Travis K. Warren,<SUP>1</SUP><SUP>, </SUP>Jay Wells,<SUP>1</SUP><SUP>, </SUP>Rekha G. Panchal,<SUP>1</SUP><SUP>, </SUP>Kelly S. Stuthman,<SUP>1</SUP><SUP>, </SUP>Nicole L. Garza,<SUP>1</SUP><SUP>, </SUP>Sean A. Van Tongeren,<SUP>1</SUP><SUP>, </SUP>Lian Dong,<SUP>1</SUP><SUP>, </SUP>Cary J. Retterer,<SUP>1</SUP><SUP>, </SUP>Brett P. Eaton,<SUP>1</SUP><SUP>, </SUP>Gianluca Pegoraro,<SUP>1</SUP><SUP>, </SUP>Shelley Honnold,<SUP>1</SUP><SUP>, </SUP>Shanta Bantia,<SUP>2</SUP><SUP>, </SUP>Pravin Kotian,<SUP>2</SUP><SUP>, </SUP>Xilin Chen,<SUP>2</SUP><SUP>, </SUP>Brian R. Taubenheim,<SUP>2, 4</SUP><SUP>, </SUP>Lisa S. Welch,<SUP>1</SUP><SUP>, </SUP>Dena M. Minning,<SUP>3</SUP><SUP>, </SUP>Yarlagadda S. Babu,<SUP>2</SUP><SUP>, </SUP>William P. Sheridan<SUP>2</SUP><SUP>, </SUP>& Sina Bavari<SUP>1</SUP>
<SUP></SUP>
Journal name: Nature - Volume: 508, Pages: 402?405 - Date published: (17 April 2014) - DOI: doi:10.1038/nature13027
Received 02 December 2012 - Accepted 13 January 2014 - Published online 02 March 2014
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.
Subject terms
harmaceutics?Antivirals?Marburg virus?Ebola virusAffiliations
1) Division of Molecular and Translational Sciences, Therapeutic Discovery Center, United States Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Maryland 21702, USA: 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, Lisa S. Welch & Sina Bavari
2) BioCryst Pharmaceuticals Inc., Durham, North Carolina 27703, USA: Shanta Bantia, Pravin Kotian, Xilin Chen, Brian R. Taubenheim, Yarlagadda S. Babu & William P. Sheridan
3) MedExpert Consulting, Inc., Indialantic, Florida 32903, USA: Dena M. Minning
Present address: Wilco Consulting, LLC, Durham, North Carolina 27712, USA.
Contributions
Y.S.B. and P.K. were responsible for the synthesis of BCX4430 and other small molecules. T.K.W. designed and supervised activities associated with rodent and non-human primate efficacy evaluations, evaluated study results, and wrote the manuscript. J.W., K.S.D., N.L.G. and S.A.V.T. conducted the rodent and non-human primate efficacy studies and performed sample analyses. R.G.P., G.P., C.J.R. and B.P.E. designed and executed cell-based filovirus assays and analysed these data. S. Bantia, Y.S.B., D.M.M., W.P.S., B.R.T. and others designed and analysed data from cell-based antiviral assays. L.D. conducted quantitative PCR analysis. B.R.T. conducted statistical evaluations of in vivo study results. S.H. performed post-mortem analysis of all non-human primate subjects. Y.S.B. supervised the pharmacokinetics studies of BCX4430 and W.P.S. conducted pharmacokinetics data analysis. S. Bantia conducted assessments of BCX4430 metabolite analysis and incorporation into host nucleic acids. X.C. conducted chain termination experiments. T.K.W., D.M.M., L.S.W., B.R.T., Y.S.B., W.P.S. and S. Bavari designed experiments, evaluated results and provided project oversight.
Competing financial interests
S. Bantia, P.K., Y.S.B. and BioCryst Pharmaceuticals, Inc. claim intellectual property regarding BCX4430 for treatment of viral infections. S. Bantia, X.C., P.K., Y.S.B. and W.P.S. are employees of BioCryst Pharmaceuticals, Inc.
-
-------