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Design and Development of a Novel Oral 4'-Fluorouridine Double Prodrug VV261 against SFTSV
Yong Cheng1,2,3, Wei Zheng4, Xinru Dong5,3
1State 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.
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.
Insights
A new drug, VV261, shows promise for treating Severe Fever with Thrombocytopenia Syndrome (SFTS). This 4’-Fluorouridine (4’-FU) prodrug offers improved stability and effectively combats SFTS virus in preclinical studies.
Area of Science:
- Virology
- Medicinal Chemistry
- Pharmacology
Background:
- Severe Fever with Thrombocytopenia Syndrome (SFTS) is a significant public health concern.
- 4'-Fluorouridine (4'-FU) exhibits potent anti-SFTSV activity but suffers from poor chemical stability, limiting its therapeutic potential.
- Developing stable and effective antiviral agents for SFTS is crucial.
Purpose of the Study:
- To design and synthesize a novel, chemically stable prodrug of 4'-FU for treating SFTS.
- To evaluate the pharmacokinetic properties and in vivo efficacy of the novel prodrug against SFTSV infection.
Main Methods:
- Synthesis of VV261, a novel double prodrug of 4'-FU with modifications on the ribose and base moieties.
- Assessment of chemical stability and pharmacokinetic profile of VV261.
- In vivo efficacy studies in SFTSV-infected mouse models, evaluating survival, viral load, and tissue pathology.
Main Results:
- VV261 demonstrated enhanced chemical stability and favorable pharmacokinetic properties compared to 4'-FU.
- Treatment with VV261 provided complete protection against lethal SFTSV infection in mice at 5 mg/kg/d for 7 days.
- Even short-term VV261 treatment (2 days) significantly reduced viral RNA and infectious titers in multiple organs and alleviated splenic lesions.
Conclusions:
- VV261 is a potent and stable 4'-FU prodrug with significant therapeutic potential for SFTS.
- VV261 has successfully advanced to Phase I clinical trials, representing a first-in-class drug candidate for SFTS treatment.
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