Mining a Kröhnke Pyridine Library for Anti-Arenavirus Activity
Several arenaviruses cause hemorrhagic fever (HF) disease in humans and represent important public health problems in their endemic regions. In addition, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus is a neglected human pathogen of clinical significance. There are no licensed arenavirus vaccines, and current antiarenavirus therapy is limited to an off-label use of ribavirin that is only partially effective. Therefore, there is an unmet need for novel therapeutics to combat human pathogenic arenaviruses, a task that will be facilitated by the identification of compounds with antiarenaviral activity that could serve as probes to identify arenavirus-host interactions suitable for targeting, as well as lead compounds to develop future antiarenaviral drugs. Screening of a combinatorial library of Krönhke pyridines identified compound KP-146 [(5-(5-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)-4′-methoxy-[1,1′-biphenyl]-3-yl)thiophene-2-carboxamide] as having strong anti-lymphocytic choriomeningitis virus (LCMV) activity in cultured cells. KP-146 did not inhibit LCMV cell entry but rather interfered with the activity of the LCMV ribonucleoprotein (vRNP) responsible for directing virus RNA replication and gene transcription, as well as with the budding process mediated by the LCMV matrix Z protein. LCMV variants with increased resistance to KP-146 did not emerge after serial passages in the presence of KP-146. Our findings support the consideration of Kröhnke pyridine scaffold as a valuable source to identify compounds that could serve as tools to dissect arenavirus-host interactions, as well as lead candidate structures to develop antiarenaviral drugs.
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ACS Publications
2018-02-06
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Subjects: | Arenavirus, Protein−protein interaction, Anti-LCMV activity, Kröhnke pyridine library, |
Online Access: | http://hdl.handle.net/10261/183315 http://dx.doi.org/10.13039/100000002 http://dx.doi.org/10.13039/501100000780 |
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dig-ipna-es-10261-1833152020-12-10T16:14:28Z Mining a Kröhnke Pyridine Library for Anti-Arenavirus Activity Miranda, Pedro O. Cubitt, Beatrice Jacob, Nicholas T. Janda, Kim D. De La Torre, Juan C. National Institutes of Health (US) European Commission Arenavirus Protein−protein interaction Anti-LCMV activity Kröhnke pyridine library Several arenaviruses cause hemorrhagic fever (HF) disease in humans and represent important public health problems in their endemic regions. In addition, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus is a neglected human pathogen of clinical significance. There are no licensed arenavirus vaccines, and current antiarenavirus therapy is limited to an off-label use of ribavirin that is only partially effective. Therefore, there is an unmet need for novel therapeutics to combat human pathogenic arenaviruses, a task that will be facilitated by the identification of compounds with antiarenaviral activity that could serve as probes to identify arenavirus-host interactions suitable for targeting, as well as lead compounds to develop future antiarenaviral drugs. Screening of a combinatorial library of Krönhke pyridines identified compound KP-146 [(5-(5-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)-4′-methoxy-[1,1′-biphenyl]-3-yl)thiophene-2-carboxamide] as having strong anti-lymphocytic choriomeningitis virus (LCMV) activity in cultured cells. KP-146 did not inhibit LCMV cell entry but rather interfered with the activity of the LCMV ribonucleoprotein (vRNP) responsible for directing virus RNA replication and gene transcription, as well as with the budding process mediated by the LCMV matrix Z protein. LCMV variants with increased resistance to KP-146 did not emerge after serial passages in the presence of KP-146. Our findings support the consideration of Kröhnke pyridine scaffold as a valuable source to identify compounds that could serve as tools to dissect arenavirus-host interactions, as well as lead candidate structures to develop antiarenaviral drugs. This research was supported by NIH/NIAID grants AI047140 and AI077719 to J.C.d.l.T. P.O.M. was supported by a fellowship from the European Union’s Seventh Framework Program FP7/2007-2013 under REA Grant Agreement No.623155. Peer Reviewed 2019-06-04T14:57:02Z 2019-06-04T14:57:02Z 2018-02-06 2019-06-04T14:57:02Z artículo http://purl.org/coar/resource_type/c_6501 doi: 10.1021/acsinfecdis.7b00236 e-issn: 2373-8227 ACS Infectious Diseases 4(5): 815-824 (2018) http://hdl.handle.net/10261/183315 10.1021/acsinfecdis.7b00236 http://dx.doi.org/10.13039/100000002 http://dx.doi.org/10.13039/501100000780 #PLACEHOLDER_PARENT_METADATA_VALUE# info:eu-repo/grantAgreement/EC/FP7/623155 Postprint https://doi.org/10.1021/acsinfecdis.7b00236 Sí none ACS Publications |
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Arenavirus Protein−protein interaction Anti-LCMV activity Kröhnke pyridine library Arenavirus Protein−protein interaction Anti-LCMV activity Kröhnke pyridine library |
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Arenavirus Protein−protein interaction Anti-LCMV activity Kröhnke pyridine library Arenavirus Protein−protein interaction Anti-LCMV activity Kröhnke pyridine library Miranda, Pedro O. Cubitt, Beatrice Jacob, Nicholas T. Janda, Kim D. De La Torre, Juan C. Mining a Kröhnke Pyridine Library for Anti-Arenavirus Activity |
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Several arenaviruses cause hemorrhagic fever (HF) disease in humans and represent important public health problems in their endemic regions. In addition, evidence indicates that the worldwide-distributed prototypic arenavirus lymphocytic choriomeningitis virus is a neglected human pathogen of clinical significance. There are no licensed arenavirus vaccines, and current antiarenavirus therapy is limited to an off-label use of ribavirin that is only partially effective. Therefore, there is an unmet need for novel therapeutics to combat human pathogenic arenaviruses, a task that will be facilitated by the identification of compounds with antiarenaviral activity that could serve as probes to identify arenavirus-host interactions suitable for targeting, as well as lead compounds to develop future antiarenaviral drugs. Screening of a combinatorial library of Krönhke pyridines identified compound KP-146 [(5-(5-(2,3-dihydrobenzo[b][1,4] dioxin-6-yl)-4′-methoxy-[1,1′-biphenyl]-3-yl)thiophene-2-carboxamide] as having strong anti-lymphocytic choriomeningitis virus (LCMV) activity in cultured cells. KP-146 did not inhibit LCMV cell entry but rather interfered with the activity of the LCMV ribonucleoprotein (vRNP) responsible for directing virus RNA replication and gene transcription, as well as with the budding process mediated by the LCMV matrix Z protein. LCMV variants with increased resistance to KP-146 did not emerge after serial passages in the presence of KP-146. Our findings support the consideration of Kröhnke pyridine scaffold as a valuable source to identify compounds that could serve as tools to dissect arenavirus-host interactions, as well as lead candidate structures to develop antiarenaviral drugs. |
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National Institutes of Health (US) |
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National Institutes of Health (US) Miranda, Pedro O. Cubitt, Beatrice Jacob, Nicholas T. Janda, Kim D. De La Torre, Juan C. |
format |
artículo |
topic_facet |
Arenavirus Protein−protein interaction Anti-LCMV activity Kröhnke pyridine library |
author |
Miranda, Pedro O. Cubitt, Beatrice Jacob, Nicholas T. Janda, Kim D. De La Torre, Juan C. |
author_sort |
Miranda, Pedro O. |
title |
Mining a Kröhnke Pyridine Library for Anti-Arenavirus Activity |
title_short |
Mining a Kröhnke Pyridine Library for Anti-Arenavirus Activity |
title_full |
Mining a Kröhnke Pyridine Library for Anti-Arenavirus Activity |
title_fullStr |
Mining a Kröhnke Pyridine Library for Anti-Arenavirus Activity |
title_full_unstemmed |
Mining a Kröhnke Pyridine Library for Anti-Arenavirus Activity |
title_sort |
mining a kröhnke pyridine library for anti-arenavirus activity |
publisher |
ACS Publications |
publishDate |
2018-02-06 |
url |
http://hdl.handle.net/10261/183315 http://dx.doi.org/10.13039/100000002 http://dx.doi.org/10.13039/501100000780 |
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