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AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model
Yellow fever virus (YFV) is a zoonotic pathogen re-emerging in parts of the world, causing a viral hemorrhagic fever associated with high mortality rates. While an effective vaccine is available, having an effective antiviral against YFV is critical against unexpected outbreaks, or when vaccination...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8812913/ https://www.ncbi.nlm.nih.gov/pubmed/35073319 http://dx.doi.org/10.1371/journal.pntd.0009937 |
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author | Lin, Kai Good, Steven S. Julander, Justin G. Weight, Abbie E. Moussa, Adel Sommadossi, Jean-Pierre |
author_facet | Lin, Kai Good, Steven S. Julander, Justin G. Weight, Abbie E. Moussa, Adel Sommadossi, Jean-Pierre |
author_sort | Lin, Kai |
collection | PubMed |
description | Yellow fever virus (YFV) is a zoonotic pathogen re-emerging in parts of the world, causing a viral hemorrhagic fever associated with high mortality rates. While an effective vaccine is available, having an effective antiviral against YFV is critical against unexpected outbreaks, or when vaccination is not recommended. We have previously identified AT-281, the free base of AT-752, an orally available double prodrug of a guanosine nucleotide analog, as a potent inhibitor of YFV in vitro, with a 50% effective concentration (EC(50)) of 0.31 μM. In hamsters infected with YFV (Jimenez strain), viremia rose about 4 log(10)-fold and serum alanine aminotransferase (ALT) 2-fold compared to sham-infected animals. Treatment with 1000 mg/kg AT-752 for 7 days, initiated 4 h prior to viral challenge, reduced viremia to below the limit of detection by day 4 post infection (pi) and returned ALT to normal levels by day 6 pi. When treatment with AT-752 was initiated 2 days pi, the virus titer and ALT dropped >2 log(10) and 53% by day 4 and 6 pi, respectively. In addition, at 21 days pi, 70–100% of the infected animals in the treatment groups survived compared to 0% of the untreated group (p<0.001). Moreover, in vivo formation of the active triphosphate metabolite AT-9010 was measured in the animal tissues, with the highest concentrations in liver and kidney, organs that are vulnerable to the virus. The demonstrated in vivo activity of AT-752 suggests that it is a promising compound for clinical development in the treatment of YFV infection. |
format | Online Article Text |
id | pubmed-8812913 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-88129132022-02-04 AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model Lin, Kai Good, Steven S. Julander, Justin G. Weight, Abbie E. Moussa, Adel Sommadossi, Jean-Pierre PLoS Negl Trop Dis Research Article Yellow fever virus (YFV) is a zoonotic pathogen re-emerging in parts of the world, causing a viral hemorrhagic fever associated with high mortality rates. While an effective vaccine is available, having an effective antiviral against YFV is critical against unexpected outbreaks, or when vaccination is not recommended. We have previously identified AT-281, the free base of AT-752, an orally available double prodrug of a guanosine nucleotide analog, as a potent inhibitor of YFV in vitro, with a 50% effective concentration (EC(50)) of 0.31 μM. In hamsters infected with YFV (Jimenez strain), viremia rose about 4 log(10)-fold and serum alanine aminotransferase (ALT) 2-fold compared to sham-infected animals. Treatment with 1000 mg/kg AT-752 for 7 days, initiated 4 h prior to viral challenge, reduced viremia to below the limit of detection by day 4 post infection (pi) and returned ALT to normal levels by day 6 pi. When treatment with AT-752 was initiated 2 days pi, the virus titer and ALT dropped >2 log(10) and 53% by day 4 and 6 pi, respectively. In addition, at 21 days pi, 70–100% of the infected animals in the treatment groups survived compared to 0% of the untreated group (p<0.001). Moreover, in vivo formation of the active triphosphate metabolite AT-9010 was measured in the animal tissues, with the highest concentrations in liver and kidney, organs that are vulnerable to the virus. The demonstrated in vivo activity of AT-752 suggests that it is a promising compound for clinical development in the treatment of YFV infection. Public Library of Science 2022-01-24 /pmc/articles/PMC8812913/ /pubmed/35073319 http://dx.doi.org/10.1371/journal.pntd.0009937 Text en © 2022 Lin et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Lin, Kai Good, Steven S. Julander, Justin G. Weight, Abbie E. Moussa, Adel Sommadossi, Jean-Pierre AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model |
title | AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model |
title_full | AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model |
title_fullStr | AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model |
title_full_unstemmed | AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model |
title_short | AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model |
title_sort | at-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8812913/ https://www.ncbi.nlm.nih.gov/pubmed/35073319 http://dx.doi.org/10.1371/journal.pntd.0009937 |
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