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Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication
The nucleoside analog N4-hydroxycytidine (NHC) is the active metabolite of the prodrug molnupiravir, which has been approved for the treatment of COVID-19. SARS-CoV-2 incorporates NHC into its RNA, resulting in defective virus genomes. Likewise, inhibitors of dihydroorotate dehydrogenase (DHODH) red...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9035612/ https://www.ncbi.nlm.nih.gov/pubmed/35492218 http://dx.doi.org/10.1016/j.isci.2022.104293 |
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author | Stegmann, Kim M. Dickmanns, Antje Heinen, Natalie Blaurock, Claudia Karrasch, Tim Breithaupt, Angele Klopfleisch, Robert Uhlig, Nadja Eberlein, Valentina Issmail, Leila Herrmann, Simon T. Schreieck, Amelie Peelen, Evelyn Kohlhof, Hella Sadeghi, Balal Riek, Alexander Speakman, John R. Groß, Uwe Görlich, Dirk Vitt, Daniel Müller, Thorsten Grunwald, Thomas Pfaender, Stephanie Balkema-Buschmann, Anne Dobbelstein, Matthias |
author_facet | Stegmann, Kim M. Dickmanns, Antje Heinen, Natalie Blaurock, Claudia Karrasch, Tim Breithaupt, Angele Klopfleisch, Robert Uhlig, Nadja Eberlein, Valentina Issmail, Leila Herrmann, Simon T. Schreieck, Amelie Peelen, Evelyn Kohlhof, Hella Sadeghi, Balal Riek, Alexander Speakman, John R. Groß, Uwe Görlich, Dirk Vitt, Daniel Müller, Thorsten Grunwald, Thomas Pfaender, Stephanie Balkema-Buschmann, Anne Dobbelstein, Matthias |
author_sort | Stegmann, Kim M. |
collection | PubMed |
description | The nucleoside analog N4-hydroxycytidine (NHC) is the active metabolite of the prodrug molnupiravir, which has been approved for the treatment of COVID-19. SARS-CoV-2 incorporates NHC into its RNA, resulting in defective virus genomes. Likewise, inhibitors of dihydroorotate dehydrogenase (DHODH) reduce virus yield upon infection, by suppressing the cellular synthesis of pyrimidines. Here, we show that NHC and DHODH inhibitors strongly synergize in the inhibition of SARS-CoV-2 replication in vitro. We propose that the lack of available pyrimidine nucleotides upon DHODH inhibition increases the incorporation of NHC into nascent viral RNA. This concept is supported by the rescue of virus replication upon addition of pyrimidine nucleosides to the media. DHODH inhibitors increased the antiviral efficiency of molnupiravir not only in organoids of human lung, but also in Syrian Gold hamsters and in K18-hACE2 mice. Combining molnupiravir with DHODH inhibitors may thus improve available therapy options for COVID-19. |
format | Online Article Text |
id | pubmed-9035612 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-90356122022-04-25 Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication Stegmann, Kim M. Dickmanns, Antje Heinen, Natalie Blaurock, Claudia Karrasch, Tim Breithaupt, Angele Klopfleisch, Robert Uhlig, Nadja Eberlein, Valentina Issmail, Leila Herrmann, Simon T. Schreieck, Amelie Peelen, Evelyn Kohlhof, Hella Sadeghi, Balal Riek, Alexander Speakman, John R. Groß, Uwe Görlich, Dirk Vitt, Daniel Müller, Thorsten Grunwald, Thomas Pfaender, Stephanie Balkema-Buschmann, Anne Dobbelstein, Matthias iScience Article The nucleoside analog N4-hydroxycytidine (NHC) is the active metabolite of the prodrug molnupiravir, which has been approved for the treatment of COVID-19. SARS-CoV-2 incorporates NHC into its RNA, resulting in defective virus genomes. Likewise, inhibitors of dihydroorotate dehydrogenase (DHODH) reduce virus yield upon infection, by suppressing the cellular synthesis of pyrimidines. Here, we show that NHC and DHODH inhibitors strongly synergize in the inhibition of SARS-CoV-2 replication in vitro. We propose that the lack of available pyrimidine nucleotides upon DHODH inhibition increases the incorporation of NHC into nascent viral RNA. This concept is supported by the rescue of virus replication upon addition of pyrimidine nucleosides to the media. DHODH inhibitors increased the antiviral efficiency of molnupiravir not only in organoids of human lung, but also in Syrian Gold hamsters and in K18-hACE2 mice. Combining molnupiravir with DHODH inhibitors may thus improve available therapy options for COVID-19. Elsevier 2022-04-25 /pmc/articles/PMC9035612/ /pubmed/35492218 http://dx.doi.org/10.1016/j.isci.2022.104293 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Stegmann, Kim M. Dickmanns, Antje Heinen, Natalie Blaurock, Claudia Karrasch, Tim Breithaupt, Angele Klopfleisch, Robert Uhlig, Nadja Eberlein, Valentina Issmail, Leila Herrmann, Simon T. Schreieck, Amelie Peelen, Evelyn Kohlhof, Hella Sadeghi, Balal Riek, Alexander Speakman, John R. Groß, Uwe Görlich, Dirk Vitt, Daniel Müller, Thorsten Grunwald, Thomas Pfaender, Stephanie Balkema-Buschmann, Anne Dobbelstein, Matthias Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication |
title | Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication |
title_full | Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication |
title_fullStr | Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication |
title_full_unstemmed | Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication |
title_short | Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication |
title_sort | inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and n4-hydroxycytidine to suppress sars-cov-2 replication |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9035612/ https://www.ncbi.nlm.nih.gov/pubmed/35492218 http://dx.doi.org/10.1016/j.isci.2022.104293 |
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