The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal venezuelan equine encephalitis virus infection
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved..
The New World alphaviruses Venezuelan, Eastern, and Western equine encephalitis viruses (VEEV, EEEV and WEEV, respectively) commonly cause a febrile disease that can progress to meningoencephalitis, resulting in significant morbidity and mortality. To address the need for a therapeutic agent for the treatment of Alphavirus infections, we identified and pursued preclinical characterization of a ribonucleoside analog EIDD-1931 (β-D-N4-hydroxycytidine, NHC), which has shown broad activity against alphaviruses in vitro and has a very high genetic barrier for development of resistance. To be truly effective as a therapeutic agent for VEEV infection a drug must penetrate the blood brain barrier and arrest virus replication in the brain. High plasma levels of EIDD-1931 are rapidly achieved in mice after oral dosing. Once in the plasma EIDD-1931 is efficiently distributed into organs, including brain, where it is rapidly converted to its active 5'-triphosphate. EIDD-1931 showed a good safety profile in mice after 7-day repeated dosing with up to 1000 mg/kg/day doses. In mouse model studies, EIDD-1931 was 90-100% effective in protecting mice against lethal intranasal infection when therapeutic treatment was started as late as 24 h post-infection, and partial protection was achieved when treatment was delayed for 48 h post-infection. These results support further preclinical development of EIDD-1931 as a potential anti-alphavirus drug.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:171 |
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| Enthalten in: |
Antiviral research - 171(2019) vom: 05. Nov., Seite 104597 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Painter, George R [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.07.2020 Date Revised 08.07.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.antiviral.2019.104597 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM301031266 |
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| 100 | 1 | |a Painter, George R |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal venezuelan equine encephalitis virus infection |
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| 520 | |a Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved. | ||
| 520 | |a The New World alphaviruses Venezuelan, Eastern, and Western equine encephalitis viruses (VEEV, EEEV and WEEV, respectively) commonly cause a febrile disease that can progress to meningoencephalitis, resulting in significant morbidity and mortality. To address the need for a therapeutic agent for the treatment of Alphavirus infections, we identified and pursued preclinical characterization of a ribonucleoside analog EIDD-1931 (β-D-N4-hydroxycytidine, NHC), which has shown broad activity against alphaviruses in vitro and has a very high genetic barrier for development of resistance. To be truly effective as a therapeutic agent for VEEV infection a drug must penetrate the blood brain barrier and arrest virus replication in the brain. High plasma levels of EIDD-1931 are rapidly achieved in mice after oral dosing. Once in the plasma EIDD-1931 is efficiently distributed into organs, including brain, where it is rapidly converted to its active 5'-triphosphate. EIDD-1931 showed a good safety profile in mice after 7-day repeated dosing with up to 1000 mg/kg/day doses. In mouse model studies, EIDD-1931 was 90-100% effective in protecting mice against lethal intranasal infection when therapeutic treatment was started as late as 24 h post-infection, and partial protection was achieved when treatment was delayed for 48 h post-infection. These results support further preclinical development of EIDD-1931 as a potential anti-alphavirus drug | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Alphavirus | |
| 650 | 4 | |a CNS penetration | |
| 650 | 4 | |a Murine model | |
| 650 | 4 | |a Ribonucleoside analog | |
| 650 | 4 | |a Therapeutic treatment | |
| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a Ribonucleosides |2 NLM | |
| 700 | 1 | |a Bowen, Richard A |e verfasserin |4 aut | |
| 700 | 1 | |a Bluemling, Gregory R |e verfasserin |4 aut | |
| 700 | 1 | |a DeBergh, John |e verfasserin |4 aut | |
| 700 | 1 | |a Edpuganti, Vindhya |e verfasserin |4 aut | |
| 700 | 1 | |a Gruddanti, Prabhakar R |e verfasserin |4 aut | |
| 700 | 1 | |a Guthrie, David B |e verfasserin |4 aut | |
| 700 | 1 | |a Hager, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Kuiper, Damien L |e verfasserin |4 aut | |
| 700 | 1 | |a Lockwood, Mark A |e verfasserin |4 aut | |
| 700 | 1 | |a Mitchell, Deborah G |e verfasserin |4 aut | |
| 700 | 1 | |a Natchus, Michael G |e verfasserin |4 aut | |
| 700 | 1 | |a Sticher, Zachary M |e verfasserin |4 aut | |
| 700 | 1 | |a Kolykhalov, Alexander A |e verfasserin |4 aut | |
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