Tecovirimat: A journey from discovery to mechanistic insights in poxvirus inhibition

Tecovirimat (ST-246 or TPOXX) is an antiviral agent developed as part of a U.S. biodefense initiative aimed at addressing Orthopoxvirus infections, including smallpox and mpox. Although smallpox was declared eradicated in 1980, the potential for its reemergence as a biothreat persists due to illegal stockpiling and the possibility of laboratory synthesis. The F13 protein, which plays a critical role in the formation of extracellular viral particles, serves as the primary target for tecovirimat, inhibiting the transition from intracellular mature viruses (IMVs) to intracellular enveloped viruses (IEVs). Recent research indicates that tecovirimat stabilizes F13 homodimers as a molecular glue, effectively disrupting viral wrapping processes. However, the identification of tecovirimat-resistant mutations, particularly in immunocompromised individuals, highlights the urgent need for ongoing monitoring and the development of next-generation antiviral therapies. Investigating the structural dynamics of F13 and its interactions with tecovirimat may provide crucial insights into overcoming resistance mechanisms and improving therapeutic efficacy.