Design and Development of a Novel Oral 4'-Fluorouridine Double Prodrug VV261 against SFTSV

  • J Med Chem. 2025 May 8;68(9):9811-9826. doi: 10.1021/acs.jmedchem.5c00626.
Yong Cheng  1  2  3 ,  Wei Zheng  4 ,  Xinru Dong  5  3 ,  Tengxiao Sun  1  2  3 ,  Mengwei Xu  5 ,  Li Xiang  1  2  3 ,  Jian Li  1  2  3 ,  Huilong Wang  2  3 ,  Xiaoqin Jian  5  3 ,  Jingjin Yu  4 ,  Pengcheng Li  4 ,  Tianwen Hu  4 ,  Guanghui Tian  4 ,  Xiangrui Jiang  2  3 ,  Leike Zhang  5  3  6 ,  Haji A Aisa  1  3  7 ,  Yuanchao Xie  2 ,  Gengfu Xiao  5  3 ,  Jingshan Shen  2  3
Affiliations
  • 1. State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences; Urumqi 830011, P. R. China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences; Shanghai 201203, P. R. China.
  • 3. University of Chinese Academy of Sciences, Beijing 100049, P. R. China.
  • 4. Vigonvita Shanghai Co., Ltd., Shanghai 201210, P. R. China.
  • 5. State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, P. R. China.
  • 6. Hubei Jiangxia Laboratory, Wuhan 430200, P. R. China.
  • 7. School of Pharmacy, Xinjiang Medical University, Urumqi 830054, P. R. China.
PMID: 40294286 DOI: 10.1021/acs.jmedchem.5c00626
Abstract

4'-Fluorouridine (4'-FU), despite demonstrating potent anti-SFTSV efficacy in vitro and in vivo, faces hindrances in its further development as a promising drug due to its weak chemical stability. Here, we report the discovery and development of VV261, a novel 4'-FU double prodrug with three isobutyryl groups on the ribose moiety and a nicotinoyloxymethyl group linked to the imide-nitrogen on the base moiety, exhibiting notable chemical stability and favorable pharmacokinetic properties. In SFTSV-infected mice, VV261 at 5 mg/kg/d for 7 days demonstrated complete protection against lethal SFTSV Infection, prevented weight loss, and even a 2 day treatment significantly reduced both viral RNA copies and infectious virus titers in multiple organs, and notably alleviated splenic tissue lesions. After further preclinical evaluations, VV261, identified as a promising candidate drug for the treatment of SFTS, has entered Phase I clinical trials in China, the first such candidate to reach this stage for SFTS.

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