Year: 2026
Type: article
Abstract: Molnupiravir is a nucleoside analogue antiviral drug against RNA viruses, including its clinical indication SARS-CoV-2. Whilst its mechanism-of-action is well defined, host factors that regulate its therapeutic responses have not been thoroughly deciphered and characterized. Here we show that uridine cytidine kinases (UCKs), key enzymes in pyrimidine salvage, effectively phosphorylate and thereby bioactivate N4-hydroxycytidine (NHC) - the active compound of molnupiravir, thus dictating its anti-SARS-CoV-2 efficacy and furthermore selectivity. In vitro, both isoforms of UCKs (UCK1 and UCK2) effectively phosphorylated NHC, where the structural basis of the catalysis was further deciphered via the first complete substrate bound co-crystal structure of UCK, i.e., UCK1-NHC-AMPPNP. In SARS-CoV-2-infected cells, UCK2 knockdown via siRNA hampered the intracellular accumulation of the tri-phosphorylated antiviral metabolite of NHC, resulting in a 10-fold reduction of the antiviral efficacy, and surprisingly, 2-fold reduction of its selectivity, which were critically recapitulated in a dose-dependent manner using a pan-UCK inhibitor. Altogether, this work underscores UCKs as pivotal players in upholding molnupiravir efficacy and therapeutic window, and furthermore as pharmacologically tractable targets for tailoring the drug response.
Source: PLoS Pathogens
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Funders: Åke Wiberg Stiftelse, Loo och Hans Ostermans Stiftelse för Medicinsk Forskning, Diamond Light Source, Cancerfonden, Fondation pour la Recherche Médicale, Karolinska Institutet, Vetenskapsrådet, Stiftelsen Lars Hiertas Minne, Barncancerfonden, Stiftelsen Clas Groschinskys Minnesfond, Stiftelsen Felix Mindus Bidrag till Leukemiforskningen, H2020 Marie Skłodowska-Curie Actions
Awards: Long noncoding RNAs: Understanding their nexus with oncogenic and tumor suppressor pathways, G1034322276, G1044278454, G1147202773, Att övervinna läkemedelsresistens vid akuta leukemier med SAMHD1-hämmare, G1603902595, G1684405982, G1896045634, G2409199353, Effektivare kemoterapi för leukemidrabbade, G3033825994, G3630533480, G3655759448, Targeting nucleotide metabolism for personalized antiviral therapy, G4223815878, G4276076832, G4305857609, Probiotic treatment versus placebo to risk newborns for prevention of infant mortality or undernutrition - a two-arm multi-center superiority randomized controlled trial, Targeting SAMHD1 to enhance existing cancer therapies, The treatment of disorders caused by defective dNTP metabolism, G5099344984, G5231506803, G5559080118, G6496448009, G6969285288, G712881263, The Botulinum neurotoxins -structure and mechanism of the most potent toxins of all, G753035471, G7789951528
OpenAlex ID: W7162812469