Research Progress and Challenges of Anti-monkeypox Virus Drugs Targeting F13 Protein.

F13 protein is highly conserved in orthopoxviruses and serves as a classic broad-spectrum antiviral target. Nevertheless, clinical trials prove tecovirimat has weak efficacy and poor resistance profile. F13 inhibitors only hinder EEV release to stop viral spread instead of suppressing replication, leaving IMV intact. Current improvements include domain optimization to enhance bioavailability, simplified pharmacophores to boost potency, skeletal editing for better solubility, novel scaffolds for virion assembly inhibition, and dual antiviral-anti-inflammatory agents. Crucially, future paradigms must break away from standalone F13 monotherapy and transition toward combination regimens─such as pairing F13 blockers with host-targeting entry/uncoating inhibitors─or developing multitarget inhibitors that interrupt the viral life cycle prior to IMV maturation by targeting DNA polymerase or transcription machinery.