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...
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ftdoajarticles:oai:doaj.org/article:8ed7f16b143b4c3195cab3f38bd25777 2023-05-15T15:13:03+02:00 AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model. Kai Lin Steven S Good Justin G Julander Abbie E Weight Adel Moussa Jean-Pierre Sommadossi 2022-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0009937 https://doaj.org/article/8ed7f16b143b4c3195cab3f38bd25777 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0009937 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009937 https://doaj.org/article/8ed7f16b143b4c3195cab3f38bd25777 PLoS Neglected Tropical Diseases, Vol 16, Iss 1, p e0009937 (2022) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2022 ftdoajarticles https://doi.org/10.1371/journal.pntd.0009937 2022-12-31T13:46:47Z 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 (EC50) of 0.31 μM. In hamsters infected with YFV (Jimenez strain), viremia rose about 4 log10-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 log10 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 16 1 e0009937 |
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Directory of Open Access Journals: DOAJ Articles |
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English |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Kai Lin Steven S Good Justin G Julander Abbie E Weight Adel Moussa Jean-Pierre Sommadossi AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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 (EC50) of 0.31 μM. In hamsters infected with YFV (Jimenez strain), viremia rose about 4 log10-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 log10 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 |
Article in Journal/Newspaper |
author |
Kai Lin Steven S Good Justin G Julander Abbie E Weight Adel Moussa Jean-Pierre Sommadossi |
author_facet |
Kai Lin Steven S Good Justin G Julander Abbie E Weight Adel Moussa Jean-Pierre Sommadossi |
author_sort |
Kai Lin |
title |
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_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_sort |
at-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2022 |
url |
https://doi.org/10.1371/journal.pntd.0009937 https://doaj.org/article/8ed7f16b143b4c3195cab3f38bd25777 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 16, Iss 1, p e0009937 (2022) |
op_relation |
https://doi.org/10.1371/journal.pntd.0009937 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0009937 https://doaj.org/article/8ed7f16b143b4c3195cab3f38bd25777 |
op_doi |
https://doi.org/10.1371/journal.pntd.0009937 |
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PLOS Neglected Tropical Diseases |
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16 |
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1 |
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e0009937 |
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