2. Academic Validation
  3. Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication

Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication

  • iScience. 2022 May 20;25(5):104293. doi: 10.1016/j.isci.2022.104293.
Kim M Stegmann 1,  Antje Dickmanns 1,  Natalie Heinen 2,  Claudia Blaurock 3,  Tim Karrasch 1,  Angele Breithaupt 3,  Robert Klopfleisch 4,  Nadja Uhlig 5,  Valentina Eberlein 5,  Leila Issmail 5,  Simon T Herrmann 6,  Amelie Schreieck 7,  Evelyn Peelen 7,  Hella Kohlhof 7,  Balal Sadeghi 8,  Alexander Riek 9,  John R Speakman 10,  Uwe Groß 11,  Dirk Görlich 12,  Daniel Vitt 7,  Thorsten Müller 6 13,  Thomas Grunwald 5,  Stephanie Pfaender 2,  Anne Balkema-Buschmann 3,  Matthias Dobbelstein 1
Affiliations

Affiliations

  • 1 Institute of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany.
  • 2 Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany.
  • 3 Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany.
  • 4 Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany.
  • 5 Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany.
  • 6 Department of Molecular Biochemistry, Ruhr University Bochum, Bochum, Germany.
  • 7 Immunic AG, Gräfelfing, Germany.
  • 8 Friedrich-Loeffler-Institut, Institute of Novel and Emerging Infectious Diseases, Greifswald-Insel Riems, Germany.
  • 9 Friedrich-Loeffler-Institut, Institute of Animal Welfare and Animal Husbandry, Celle, Germany.
  • 10 Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen, UK.
  • 11 Institute of Medical Microbiology and Virology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen, Germany.
  • 12 Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
  • 13 Institute of Psychiatric Phenomics and Genomics (IPPG), Organoid Laboratory, University Hospital, LMU Munich, Munich, Germany.
PMID: 35492218 DOI: 10.1016/j.isci.2022.104293
Abstract

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.

Keywords

Drugs; Virology.

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