TY - JOUR
AU - Stegmann, Kim M.
AU - Dickmanns, Antje
AU - Heinen, Natalie
AU - Blaurock, Claudia
AU - Karrasch, Tim
AU - Breithaupt, Angele
AU - Klopfleisch, Robert
AU - Uhlig, Nadja
AU - Eberlein, Valentina
AU - Issmail, Leila
AU - Herrmann, Simon T.
AU - Schreieck, Amelie
AU - Peelen, Evelyn
AU - Kohlhof, Hella
AU - Sadeghi, Balal
AU - Riek, Alexander
AU - Speakman, John R.
AU - Groß, Uwe
AU - Görlich, Dirk
AU - Vitt, Daniel
AU - Müller, Thorsten
AU - Grunwald, Thomas
AU - Pfaender, Stephanie
AU - Balkema-Buschmann, Anne
AU - Dobbelstein, Matthias
PY - 2023
DA - April
TI - Inhibitors of dihydroorotate dehydrogenase cooperate with molnupiravir and N4-hydroxycytidine to suppress SARS-CoV-2 replication
JO - iScience
VL - 25
IS - 5
DO - https://doi.org/10.1016/j.isci.2022.104293
AB - 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.
PB - Elsevier
UR - https://hdl.handle.net/2164/20828
KW - Coronavirus (COVID-19)
ER