Preclinical Characterization of PC786, an Inhaled Small-Molecule Respiratory Syncytial Virus L Protein Polymerase Inhibitor
| العنوان: | Preclinical Characterization of PC786, an Inhaled Small-Molecule Respiratory Syncytial Virus L Protein Polymerase Inhibitor |
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| المؤلفون: | John P. DeVincenzo, Young-In Kim, Guillaume F. Parra, Daniel W. Brookes, Euan A. F. Fordyce, Claire-Lise Ciana, Vladimir Sherbukhin, Kazuhiro Ito, Pete Strong, Jennifer A. Stockwell, Garth Rapeport, Matthew Coates, Peter John Murray, S. Fraser Hunt, Elizabeth A. Meals, Lindsey Cass, Jennifer C. Thomas, Thomas Colley, Stuart Thomas Onions, Lauren Anderson-Dring, Heather Allen |
| المصدر: | Antimicrobial Agents and Chemotherapy |
| بيانات النشر: | American Society for Microbiology, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, viruses, respiratory syncytial virus, 030106 microbiology, Antiviral Agents, PC786, Virus, 03 medical and health sciences, Multiplicity of infection, clinical isolate, In vivo, Lower respiratory tract infection, bronchial epithelial cell, medicine, Pharmacology (medical), Cytotoxicity, IC50, Pharmacology, inhalation, Chemistry, RNA polymerases, medicine.disease, Virology, In vitro, polymerase, Infectious Diseases, Viral replication, L protein |
| الوصف: | 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 ], 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. |
| اللغة: | English |
| تدمد: | 1098-6596 0066-4804 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6aa54caa466846b5a19adf151dd2fca7Test http://europepmc.org/articles/PMC5571287Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6aa54caa466846b5a19adf151dd2fca7 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10986596 00664804 |
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