2. Academic Validation
  3. Identification of 4'-Thiouridine as an Orally Available Antiviral Agent Targeting Both RdRp and NiRAN Functions of SARS-CoV-2 Nsp12

Identification of 4'-Thiouridine as an Orally Available Antiviral Agent Targeting Both RdRp and NiRAN Functions of SARS-CoV-2 Nsp12

  • J Med Chem. 2025 Jun 26;68(12):12414-12433. doi: 10.1021/acs.jmedchem.4c02874.
Minjae Kim 1,  Myoung Kyu Lee 2,  Inseong Jo 2,  Yejin Jang 2,  Soo Bong Han 2 3,  Juyeon Lee 2,  Ayeon Yang 1,  Dnyandev B Jarhad 1,  Hongseok Choi 1,  Yuhei Nogi 4,  Noriko Saito-Tarashima 4,  Noriaki Minakawa 4,  Meehyein Kim 2,  Lak Shin Jeong 1 5
Affiliations

Affiliations

  • 1 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
  • 2 Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology (KRICT), Daejeon 34114, Republic of Korea.
  • 3 Department of Medicinal Chemistry and Pharmacology, University of Science and Technology (UST), Daejeon 34113, Republic of Korea.
  • 4 Graduate School of Pharmaceutical Science, Tokushima University, Tokushima 770-8505, Japan.
  • 5 Future Medicine Co., Ltd, 54 Changup-ro, Sujeong-gu, Seongnam, Gyeonggi-do 13449, Republic of Korea.
PMID: 40512093 DOI: 10.1021/acs.jmedchem.4c02874
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.

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