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

Authors: 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 Grünwald, Stephanie Pfaender, Anne Balkema‐Buschmann, Matthias Dobbelstein - iScience 2022 cited by 41

. 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.