An orally available 4'-fluorouridine prodrug inhibits SFTSV and LCMV infection
文献类型：期刊论文
| 作者 | Jian, Xiaoqin1,2; Hu, Tianwen3; Xu, Huan4; Wen, Yuxi4; Zhang, Yumin1; Xu, Mengwei1; Jiang, Xiaming1; Cao, Junyuan1,5; Xiang, Li6; Shen, Jingshan2,6 |
| 刊名 | JOURNAL OF VIROLOGY
 |
| 出版日期 | 2025-09-16 |
| 页码 | 18 |
| 关键词 | severe fever with thrombocytopenia syndrome virus
lymphocytic choriomeningitis virus
4 |
| ISSN号 | 0022-538X |
| DOI | 10.1128/jvi.01172-25 |
| 英文摘要 | Bunyaviruses, a subset of segmented negative-sense RNA viruses, include pathogenic species capable of zoonotic transmission to humans via arthropod vectors and rodent hosts. Pathogenic bunyavirus infections can cause severe hemorrhagic fevers and other life-threatening diseases, posing threats to human health and social stability; however, therapeutic strategies for treating bunyavirus infections remain limited. Here, we report that VV251 hydrochloride salt (VV251), an optimized oral prodrug derivative of 4 '-fluorouridine (EIDD-2794), exhibits potent efficacy against severe fever with thrombocytopenia syndrome virus (SFTSV) and lymphocytic choriomeningitis virus (LCMV) both in vitro and in vivo. In various cell lines, VV251 inhibits SFTSV and LCMV with EC50 values in the nanomolar to micromolar range. In lethal rodent models, once-daily oral administration of VV251 at low doses (10 mg/kg for SFTSV; 1 mg/kg for LCMV) achieves complete protection (100% survival), matching the efficacy of T-705 at 300 mg/kg. Additional pharmacokinetic analysis indicates that VV251 has favorable absorption and exposure profiles in both Sprague-Dawley rat and cynomolgus monkey models. This study evaluates the antiviral profile of VV251 and supports its further development as a promising therapeutic candidate.IMPORTANCEBunyaviruses encompass numerous highly pathogenic agents that pose significant threats to human health, including the causative agents of Crimean-Congo hemorrhagic fever, Lassa fever, and Rift Valley fever. The World Health Organization has identified Lassa fever as a priority pathogen requiring urgent research and development efforts in emergency contexts, underscoring the critical need for effective oral antiviral therapies to enhance pandemic preparedness. Here, we report that VV251 hydrochloride salt (VV251), an optimized oral prodrug derivative of 4 '-fluorouridine (4 '-FlU, EIDD-2794), shows significant efficacy against severe fever with thrombocytopenia syndrome virus and lymphocytic choriomeningitis virus infections, with inhibitory activity in cell culture and protective effects in lethal animal models. Building on the established broad-spectrum antiviral activity of 4 '-FlU against multiple high-consequence pathogens (including severe acute respiratory syndrome coronavirus 2, respiratory syncytial virus, Lassa virus, and Junin virus), VV251 emerges as a promising next-generation oral antiviral candidate, offering an orally available therapeutic option to combat these formidable pathogens. |
| WOS关键词 | SEVERE FEVER ; THROMBOCYTOPENIA SYNDROME ; VIRUS-INFECTION ; BUNYAVIRUS ; RIBAVIRIN ; T-705 |
| 资助项目 | National Natural Science Foundation of China |
| WOS研究方向 | Virology |
| 语种 | 英语 |
| WOS记录号 | WOS:001571714700001 |
| 出版者 | AMER SOC MICROBIOLOGY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321447]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Tian, Guanghui; Xiao, Gengfu; Zhang, Leike |
| 作者单位 | 1.Chinese Acad Sci, Wuhan Inst Virol, Ctr Biosafety Mega Sci, State Key Lab Virol & Biosafety, Wuhan, Hubei, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.Vigonvita Shanghai Co Ltd, Shanghai, Peoples R China 4.Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Pediat, Wuhan, Peoples R China 5.Hubei Jiangxia Lab, Wuhan, Peoples R China 6.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Jian, Xiaoqin,Hu, Tianwen,Xu, Huan,et al. An orally available 4'-fluorouridine prodrug inhibits SFTSV and LCMV infection[J]. JOURNAL OF VIROLOGY,2025:18. |
| APA | Jian, Xiaoqin.,Hu, Tianwen.,Xu, Huan.,Wen, Yuxi.,Zhang, Yumin.,...&Zhang, Leike.(2025).An orally available 4'-fluorouridine prodrug inhibits SFTSV and LCMV infection.JOURNAL OF VIROLOGY,18. |
| MLA | Jian, Xiaoqin,et al."An orally available 4'-fluorouridine prodrug inhibits SFTSV and LCMV infection".JOURNAL OF VIROLOGY (2025):18. |
入库方式： OAI收割
来源：上海药物研究所
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