Efficacy of an isoxazole-3-carboxamide analog of pleconaril in mouse models of Enterovirus-D68 and Coxsackie B5
Copyright © 2023 Elsevier B.V. All rights reserved..
Enteroviruses (EV) cause a number of life-threatening infectious diseases. EV-D68 is known to cause respiratory illness in children that can lead to acute flaccid myelitis. Coxsackievirus B5 (CVB5) is commonly associated with hand-foot-mouth disease. There is no antiviral treatment available for either. We have developed an isoxazole-3-carboxamide analog of pleconaril (11526092) which displayed potent inhibition of EV-D68 (IC50 58 nM) as well as other enteroviruses including the pleconaril-resistant Coxsackievirus B3-Woodruff (IC50 6-20 nM) and CVB5 (EC50 1 nM). Cryo-electron microscopy structures of EV-D68 in complex with 11526092 and pleconaril demonstrate destabilization of the EV-D68 MO strain VP1 loop, and a strain-dependent effect. A mouse respiratory model of EV-D68 infection, showed 3-log decreased viremia, favorable cytokine response, as well as statistically significant 1-log reduction in lung titer reduction at day 5 after treatment with 11526092. An acute flaccid myelitis neurological infection model did not show efficacy. 11526092 was tested in a mouse model of CVB5 infection and showed a 4-log TCID50 reduction in the pancreas. In summary, 11526092 represents a potent in vitro inhibitor of EV with in vivo efficacy in EV-D68 and CVB5 animal models suggesting it is worthy of further evaluation as a potential broad-spectrum antiviral therapeutic against EV.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:216 |
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| Enthalten in: |
Antiviral research - 216(2023) vom: 15. Aug., Seite 105654 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lane, Thomas R [VerfasserIn] |
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| Links: |
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| Themen: |
9H4570Q89D |
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| Anmerkungen: |
Date Completed 01.08.2023 Date Revised 03.10.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.antiviral.2023.105654 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM358294479 |
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| 100 | 1 | |a Lane, Thomas R |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Efficacy of an isoxazole-3-carboxamide analog of pleconaril in mouse models of Enterovirus-D68 and Coxsackie B5 |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier B.V. All rights reserved. | ||
| 520 | |a Enteroviruses (EV) cause a number of life-threatening infectious diseases. EV-D68 is known to cause respiratory illness in children that can lead to acute flaccid myelitis. Coxsackievirus B5 (CVB5) is commonly associated with hand-foot-mouth disease. There is no antiviral treatment available for either. We have developed an isoxazole-3-carboxamide analog of pleconaril (11526092) which displayed potent inhibition of EV-D68 (IC50 58 nM) as well as other enteroviruses including the pleconaril-resistant Coxsackievirus B3-Woodruff (IC50 6-20 nM) and CVB5 (EC50 1 nM). Cryo-electron microscopy structures of EV-D68 in complex with 11526092 and pleconaril demonstrate destabilization of the EV-D68 MO strain VP1 loop, and a strain-dependent effect. A mouse respiratory model of EV-D68 infection, showed 3-log decreased viremia, favorable cytokine response, as well as statistically significant 1-log reduction in lung titer reduction at day 5 after treatment with 11526092. An acute flaccid myelitis neurological infection model did not show efficacy. 11526092 was tested in a mouse model of CVB5 infection and showed a 4-log TCID50 reduction in the pancreas. In summary, 11526092 represents a potent in vitro inhibitor of EV with in vivo efficacy in EV-D68 and CVB5 animal models suggesting it is worthy of further evaluation as a potential broad-spectrum antiviral therapeutic against EV | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Antiviral | |
| 650 | 4 | |a Coxsackievirus B5 | |
| 650 | 4 | |a Cryo-electron microscopy | |
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| 700 | 1 | |a Sherry, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a Tarbet, Bart |e verfasserin |4 aut | |
| 700 | 1 | |a Hurst, Brett L |e verfasserin |4 aut | |
| 700 | 1 | |a Riabova, Olga |e verfasserin |4 aut | |
| 700 | 1 | |a Kazakova, Elena |e verfasserin |4 aut | |
| 700 | 1 | |a Egorova, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Clarke, Penny |e verfasserin |4 aut | |
| 700 | 1 | |a Leser, J Smith |e verfasserin |4 aut | |
| 700 | 1 | |a Frost, Joshua |e verfasserin |4 aut | |
| 700 | 1 | |a Rudy, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Tyler, Kenneth L |e verfasserin |4 aut | |
| 700 | 1 | |a Klose, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Volobueva, Alexandrina S |e verfasserin |4 aut | |
| 700 | 1 | |a Belyaevskaya, Svetlana V |e verfasserin |4 aut | |
| 700 | 1 | |a Zarubaev, Vladimir V |e verfasserin |4 aut | |
| 700 | 1 | |a Kuhn, Richard J |e verfasserin |4 aut | |
| 700 | 1 | |a Makarov, Vadim |e verfasserin |4 aut | |
| 700 | 1 | |a Ekins, Sean |e verfasserin |4 aut | |
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