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Preclinical Characterization of PC786, an Inhaled Small-Molecule Respiratory Syncytial Virus L Protein Polymerase Inhibitor

Although respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and young children, attempts to develop an effective therapy have so far proved unsuccessful. Here we report the preclinical profiles of PC786, a potent nonnucleoside RSV L protein pol...

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Autores principales: Coates, Matthew, Brookes, Daniel, Kim, Young-In, Allen, Heather, Fordyce, Euan A. F., Meals, Elizabeth A., Colley, Thomas, Ciana, Claire-Lise, Parra, Guillaume F., Sherbukhin, Vladimir, Stockwell, Jennifer A., Thomas, Jennifer C., Hunt, S. Fraser, Anderson-Dring, Lauren, Onions, Stuart T., Cass, Lindsey, Murray, Peter J., Ito, Kazuhiro, Strong, Pete, DeVincenzo, John P., Rapeport, Garth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571287/
https://www.ncbi.nlm.nih.gov/pubmed/28652242
http://dx.doi.org/10.1128/AAC.00737-17
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author Coates, Matthew
Brookes, Daniel
Kim, Young-In
Allen, Heather
Fordyce, Euan A. F.
Meals, Elizabeth A.
Colley, Thomas
Ciana, Claire-Lise
Parra, Guillaume F.
Sherbukhin, Vladimir
Stockwell, Jennifer A.
Thomas, Jennifer C.
Hunt, S. Fraser
Anderson-Dring, Lauren
Onions, Stuart T.
Cass, Lindsey
Murray, Peter J.
Ito, Kazuhiro
Strong, Pete
DeVincenzo, John P.
Rapeport, Garth
author_facet Coates, Matthew
Brookes, Daniel
Kim, Young-In
Allen, Heather
Fordyce, Euan A. F.
Meals, Elizabeth A.
Colley, Thomas
Ciana, Claire-Lise
Parra, Guillaume F.
Sherbukhin, Vladimir
Stockwell, Jennifer A.
Thomas, Jennifer C.
Hunt, S. Fraser
Anderson-Dring, Lauren
Onions, Stuart T.
Cass, Lindsey
Murray, Peter J.
Ito, Kazuhiro
Strong, Pete
DeVincenzo, John P.
Rapeport, Garth
author_sort Coates, Matthew
collection PubMed
description Although respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and young children, attempts to develop an effective therapy have so far proved unsuccessful. Here we report the preclinical profiles of PC786, a potent nonnucleoside RSV L protein polymerase inhibitor, designed for inhalation treatment of RSV infection. PC786 demonstrated a potent and selective antiviral activity against laboratory-adapted or clinical isolates of RSV-A (50% inhibitory concentration [IC(50)], <0.09 to 0.71 nM) and RSV-B (IC(50), 1.3 to 50.6 nM), which were determined by inhibition of cytopathic effects in HEp-2 cells without causing detectable cytotoxicity. The underlying inhibition of virus replication was confirmed by PCR analysis. The effects of PC786 were largely unaffected by the multiplicity of infection (MOI) and were retained in the face of established RSV replication in a time-of-addition study. Persistent anti-RSV effects of PC786 were also demonstrated in human bronchial epithelial cells. In vivo intranasal once daily dosing with PC786 was able to reduce the virus load to undetectable levels in lung homogenates from RSV-infected mice and cotton rats. Treatment with escalating concentrations identified a dominant mutation in the L protein (Y1631H) in vitro. In addition, PC786 potently inhibited RSV RNA-dependent RNA polymerase (RdRp) activity in a cell-free enzyme assay and minigenome assay in HEp-2 cells (IC(50), 2.1 and 0.5 nM, respectively). Thus, PC786 was shown to be a potent anti-RSV agent via inhibition of RdRp activity, making topical treatment with this compound a novel potential therapy for the treatment of human RSV infections.
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spelling pubmed-55712872017-09-05 Preclinical Characterization of PC786, an Inhaled Small-Molecule Respiratory Syncytial Virus L Protein Polymerase Inhibitor Coates, Matthew Brookes, Daniel Kim, Young-In Allen, Heather Fordyce, Euan A. F. Meals, Elizabeth A. Colley, Thomas Ciana, Claire-Lise Parra, Guillaume F. Sherbukhin, Vladimir Stockwell, Jennifer A. Thomas, Jennifer C. Hunt, S. Fraser Anderson-Dring, Lauren Onions, Stuart T. Cass, Lindsey Murray, Peter J. Ito, Kazuhiro Strong, Pete DeVincenzo, John P. Rapeport, Garth Antimicrob Agents Chemother Antiviral Agents Although respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and young children, attempts to develop an effective therapy have so far proved unsuccessful. Here we report the preclinical profiles of PC786, a potent nonnucleoside RSV L protein polymerase inhibitor, designed for inhalation treatment of RSV infection. PC786 demonstrated a potent and selective antiviral activity against laboratory-adapted or clinical isolates of RSV-A (50% inhibitory concentration [IC(50)], <0.09 to 0.71 nM) and RSV-B (IC(50), 1.3 to 50.6 nM), which were determined by inhibition of cytopathic effects in HEp-2 cells without causing detectable cytotoxicity. The underlying inhibition of virus replication was confirmed by PCR analysis. The effects of PC786 were largely unaffected by the multiplicity of infection (MOI) and were retained in the face of established RSV replication in a time-of-addition study. Persistent anti-RSV effects of PC786 were also demonstrated in human bronchial epithelial cells. In vivo intranasal once daily dosing with PC786 was able to reduce the virus load to undetectable levels in lung homogenates from RSV-infected mice and cotton rats. Treatment with escalating concentrations identified a dominant mutation in the L protein (Y1631H) in vitro. In addition, PC786 potently inhibited RSV RNA-dependent RNA polymerase (RdRp) activity in a cell-free enzyme assay and minigenome assay in HEp-2 cells (IC(50), 2.1 and 0.5 nM, respectively). Thus, PC786 was shown to be a potent anti-RSV agent via inhibition of RdRp activity, making topical treatment with this compound a novel potential therapy for the treatment of human RSV infections. American Society for Microbiology 2017-08-24 /pmc/articles/PMC5571287/ /pubmed/28652242 http://dx.doi.org/10.1128/AAC.00737-17 Text en Copyright © 2017 Coates et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Antiviral Agents
Coates, Matthew
Brookes, Daniel
Kim, Young-In
Allen, Heather
Fordyce, Euan A. F.
Meals, Elizabeth A.
Colley, Thomas
Ciana, Claire-Lise
Parra, Guillaume F.
Sherbukhin, Vladimir
Stockwell, Jennifer A.
Thomas, Jennifer C.
Hunt, S. Fraser
Anderson-Dring, Lauren
Onions, Stuart T.
Cass, Lindsey
Murray, Peter J.
Ito, Kazuhiro
Strong, Pete
DeVincenzo, John P.
Rapeport, Garth
Preclinical Characterization of PC786, an Inhaled Small-Molecule Respiratory Syncytial Virus L Protein Polymerase Inhibitor
title Preclinical Characterization of PC786, an Inhaled Small-Molecule Respiratory Syncytial Virus L Protein Polymerase Inhibitor
title_full Preclinical Characterization of PC786, an Inhaled Small-Molecule Respiratory Syncytial Virus L Protein Polymerase Inhibitor
title_fullStr Preclinical Characterization of PC786, an Inhaled Small-Molecule Respiratory Syncytial Virus L Protein Polymerase Inhibitor
title_full_unstemmed Preclinical Characterization of PC786, an Inhaled Small-Molecule Respiratory Syncytial Virus L Protein Polymerase Inhibitor
title_short Preclinical Characterization of PC786, an Inhaled Small-Molecule Respiratory Syncytial Virus L Protein Polymerase Inhibitor
title_sort preclinical characterization of pc786, an inhaled small-molecule respiratory syncytial virus l protein polymerase inhibitor
topic Antiviral Agents
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571287/
https://www.ncbi.nlm.nih.gov/pubmed/28652242
http://dx.doi.org/10.1128/AAC.00737-17
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