@article{Stegmann_K-2023_138809,
title = {Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication},
author = {Stegmann, K. and Dickmanns, A. and Heinen, N. and Blaurock, C. and Karrasch, T. and Breithaupt, A. and Klopfleisch, R. and Uhlig, N. and Eberlein, V. and Issmail, L. and Herrmann, S. and Schreieck, A. and Peelen, E. and Kohlhof, H. and Sadeghi, B. and Riek, A. and Speakman, J. and Groß, U. and Görlich, D. and Vitt, D. and Müller, T. and Grunwald, T. and Pfaender, S. and Balkema-Buschmann, A. and Dobbelstein, M.},
month = {apr},
year = {2023},
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 replicationin 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.},
volume = {25},
issue = {5},
journal = {iScience},
publisher = {Elsevier},
url = {https://doi.org/10.1016/j.isci.2022.104293},
}
