Small-Molecule Antivirals against Severe Fever with Thrombocytopenia Syndrome Virus: From Viral Life Cycle Targets to Host-Directed Strategies

Abstract

Severe fever with thrombocytopenia syndrome virus (SFTSV), an emerging tick-borne bunyavirus with a case fatality rate of up to 30%, poses a growing threat to global public health. No approved specific antivirals are currently available. This perspective critically evaluates recent advances in the development of small-molecule anti-SFTSV agents, organized through a dual framework encompassing both viral life cycle targets and host-dependent pathways. We highlight direct-acting antivirals targeting key viral components, including viral entry glycoproteins (Gc/Gn proteins), cap-snatching endonuclease, RNA-dependent RNA polymerase (RdRp), and nucleoprotein (NP), as well as host-directed therapies modulating critical cellular pathways. Notable candidates include the clinical-stage prodrug VV261 and calcium channel blockers with proven in vivo efficacy and retrospective clinical evidence. By integrating molecular mechanistic insights with translational progress, this perspective provides a comprehensive reference for accelerating the development and clinical translation of small-molecule therapeutics against SFTSV.