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N4-hydroxycytidine, the active compound of Molnupiravir, promotes SARS-CoV-2 mutagenesis and escape from a neutralizing nanobody

Zibat et al., iScience, doi:10.1016/j.isci.2023.107786
Aug 2023  
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In Vitro study showing that NHC, the active compound molnupiravir, can promote rapid selection of immune escape mutants. NHC treatment enabled selection of nanobody-resistant mutants much faster than without NHC. While an in vitro model with limitations, these results provide additional evidence that molnupiravir facilitates the emergence of new SARS-CoV-2 variants.
Authors note that combined use with other antivirals like paxlovid may create variants resistant to those antivirals.
Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer Hadj Hassine, Huntsman, Marikawa, Swanstrom, Waters, Zibat. Multiple analyses have identifed variants potentially created by molnupiravir Fountain-Jones, Sanderson,
Zibat et al., 31 Aug 2023, Germany, peer-reviewed, 13 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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N4-hydroxycytidine, the active compound of Molnupiravir, promotes SARS-CoV-2 mutagenesis and escape from a neutralizing nanobody
Arne Zibat, Xiaoxiao Zhang, Antje Dickmanns, Kim M Stegmann, Adrian Dobbelstein, Halima Alachram, Rebecca Soliwoda, Gabriela Salinas, Uwe Groß, Dirk Görlich, Maik Kschischo, Bernd Wollnik, Matthias Dobbelstein
iScience, doi:10.1016/j.isci.2023.107786
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
J o u r n a l P r e -p r o o f additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. • This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request. EXPERIMENTAL MODEL AND STUDY PARTICIPANT DETAILS Vero E6 cells (Vero C1008) were obtained from the German Primate Research Center Göttingen. Cells were maintained in Dulbecco's modified Eagle's medium (DMEM with GlutaMAX TM , Gibco) supplemented with 10% fetal bovine serum (FBS; Merck), 50 units/mL penicillin, 50 μg/mL streptomycin (Gibco), 2 µg/mL tetracycline (Sigma) and 10 µg/mL ciprofloxacin (Bayer) at 37°C in a humidified atmosphere with 5% CO2. Vero E6 cells were authenticated in 2021 by means of Cytochrome C Subunit I (COI) DNA Barcoding by the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ). Furthermore, the cells were routinely tested to ensure they were negative for mycoplasma contamination, using the MycoAlert Assay Control Set (Lonza). J o u r n a l P r e -p r o o f
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