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Updated: Jun 14, 2025
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Identification of 4'-Thiouridine as an Orally Available Antiviral Agent Targeting Both RdRp and NiRAN Functions of
Minjae Kim1, Myoung Kyu Lee2, Inseong Jo2
1Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Abstract:
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 EC50 value of 1.71 μM and a CC50 value exceeding 100 μM. Its triphosphate metabolite, compound 8, inhibited the RNA-dependent RNA polymerase activity of the SARS-CoV-2 Nsp12-Nsp7-Nsp82 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.
