Key result
Oral 4′-thiouridine yields ~40% survival and near-complete weight recovery in mice with lethal SARS-CoV-2.
Why the study?
Does 4′-thiouridine protect against SARS-CoV-2 infection in preclinical models?
Does 4′-thiouridine protect against SARS-CoV-2 infection in preclinical models?
4′-thiouridine is a promising orally available antiviral candidate that targets both RdRp and NiRAN functions of SARS-CoV-2 Nsp12.
Hypothesis-generating for oral 4′-thiouridine against coronaviruses; human trials needed before any clinical consideration.
Through screening of a nucleos(t)ide-focused chemical library, we identified 4′-thiouridine ( 1 ) as a potent antiviral agent against SARS-CoV-2 in Vero cells, with an EC 50 value of 1.71 μM and a CC 50 value exceeding 100 μM. Its triphosphate metabolite, compound 8, inhibited the RNA-dependent RNA polymerase activity of the SARS-CoV-2 Nsp12-Nsp7-Nsp8 2 complex, terminating nascent RNA synthesis through misincorporation. Additionally, compound 8 suppressed the function of the NiRAN domain of Nsp12, effectively blocking both RNAylation and NMPylation of Nsp9. Pharmacokinetic analysis in mice showed excellent oral bioavailability of compound 1 . Oral administration at 100 mg/kg/day, twice daily for 5 days, protected mice from lethal SARS-CoV-2 infection, resulting in 40% survival and near-complete recovery of body weight by day 14 postinfection. Compound 1 also exhibited broad-spectrum activity against various coronaviruses and other RNA viruses. These findings highlight that compound 1 is a promising orally available antiviral candidate.
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Kim et al. (2025) studied SARS-CoV-2 infection. 4′-thiouridine was evaluated on Survival. Oral administration of 4′-thiouridine (100 mg/kg/day) protected mice from lethal SARS-CoV-2 infection, resulting in 40% survival and near-complete recovery of body weight by day 14.
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