Design and Development of a Novel Oral 4′-Fluorouridine Double Prodrug VV261 against SFTSV
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.
Authors
- Tengxiao Sun
- Jingshan Shen (ORCID: https://orcid.org/0000-0001-9679-9934)
- Yuanchao Xie (ORCID: https://orcid.org/0000-0001-9875-887X)
- Hui‐Long Wang (ORCID: https://orcid.org/0000-0003-4207-1109)
- Haji Akber Aisa (ORCID: https://orcid.org/0000-0003-4652-6879)
- Tianwen Hu (ORCID: https://orcid.org/0000-0003-2997-8232)
- Xiaoqin Jian
- Xinru Dong
- Mengwei Xu (ORCID: https://orcid.org/0000-0003-4978-3061)
- Leike Zhang (ORCID: https://orcid.org/0000-0002-2593-2571)
- Xiangrui Jiang (ORCID: https://orcid.org/0000-0001-5941-6105)
- Jingjin Yu
- Cheng Yong
- Xiang Li (ORCID: https://orcid.org/0000-0002-0016-6233)
- Jian Li (ORCID: https://orcid.org/0000-0001-9511-4219)
- Wei Zheng (ORCID: https://orcid.org/0000-0003-4276-2006)
- Tian Guang-hui
- Gengfu Xiao
- Pengcheng Li (ORCID: https://orcid.org/0000-0002-9653-5194)
Institutions
- Xinjiang Medical University (CN)
- Chinese Academy of Sciences (CN)
- Xinjiang Technical Institute of Physics & Chemistry (CN)
- Wuhan Institute of Virology (CN)
- Shanghai Institute of Materia Medica (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-04-28
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00626
- Citations
- 6
- Primary Topic
- Viral Infections and Vectors
- Type
- article
- Field-Weighted Citation Impact
- 8.38
Funders
- Chinese Academy of Sciences
- National Key Research and Development Program of China
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences
- Science Fund for Distinguished Young Scholars of Hubei Province