VV-261

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.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne bunyavirus with a mortality rate of up to 30%. There is no specific treatment for SFTSV. This article systematically reviews the progress of major anti-SFTSV drugs. The nucleotide analogues (favipiravir, 4′-fluorouridine diphosphate prodrug VV261) have shown clinical potential. Calcium channel blockers (nifedipine, etc.) block virus invasion by inhibiting calcium influx. Monoclonal antibody (S2A5/SNB02) has achieved targeted therapy, and SNB02 nanoantibody has entered clinical trials. However, many candidate agents predominantly focus on a single target, such as viral RdRp or host calcium channels, which makes it difficult to block the entire viral replication cycle and may accelerate the accumulation of resistant mutations. In addition, the low bioavailability of small-molecule drugs, the obstacles to industrial-scale production of antibody-based therapies, and the lack of Phase III clinical evidence severely restrict their clinical translation. Future research should focus on exploring viral replication mechanisms, developing drugs against key viral proteins, and designing multi-target combination therapies and novel drug delivery systems.