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.