iScience (May 2022)
Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication
- Kim M. Stegmann,
- Antje Dickmanns,
- Natalie Heinen,
- Claudia Blaurock,
- Tim Karrasch,
- Angele Breithaupt,
- Robert Klopfleisch,
- Nadja Uhlig,
- Valentina Eberlein,
- Leila Issmail,
- Simon T. Herrmann,
- Amelie Schreieck,
- Evelyn Peelen,
- Hella Kohlhof,
- Balal Sadeghi,
- Alexander Riek,
- John R. Speakman,
- Uwe Groß,
- Dirk Görlich,
- Daniel Vitt,
- Thorsten Müller,
- Thomas Grunwald,
- Stephanie Pfaender,
- Anne Balkema-Buschmann,
- Matthias Dobbelstein
Affiliations
- Kim M. Stegmann
- Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany
- Antje Dickmanns
- Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany
- Natalie Heinen
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Claudia Blaurock
- Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany
- Tim Karrasch
- Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany
- Angele Breithaupt
- Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany
- Robert Klopfleisch
- Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany
- Nadja Uhlig
- Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany
- Valentina Eberlein
- Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany
- Leila Issmail
- Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany
- Simon T. Herrmann
- Department of Molecular Biochemistry, Ruhr University Bochum, Bochum, Germany
- Amelie Schreieck
- Immunic AG, Gräfelfing, Germany
- Evelyn Peelen
- Immunic AG, Gräfelfing, Germany
- Hella Kohlhof
- Immunic AG, Gräfelfing, Germany
- Balal Sadeghi
- Friedrich-Loeffler-Institut, Institute of Novel and Emerging Infectious Diseases, Greifswald-Insel Riems, Germany
- Alexander Riek
- Friedrich-Loeffler-Institut, Institute of Animal Welfare and Animal Husbandry, Celle, Germany
- John R. Speakman
- Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK
- Uwe Groß
- Institute of Medical Microbiology and Virology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen, Germany
- Dirk Görlich
- Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
- Daniel Vitt
- Immunic AG, Gräfelfing, Germany
- Thorsten Müller
- Department of Molecular Biochemistry, Ruhr University Bochum, Bochum, Germany; Institute of Psychiatric Phenomics and Genomics (IPPG), Organoid Laboratory, University Hospital, LMU Munich, Munich, Germany
- Thomas Grunwald
- Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany
- Stephanie Pfaender
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
- Anne Balkema-Buschmann
- Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany
- Matthias Dobbelstein
- Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany; Corresponding author
- Journal volume & issue
-
Vol. 25,
no. 5
p. 104293
Abstract
Summary: 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.
