Low-Molecular-Weight Inhibitors of Orthopoxviruses: Targets, Mechanisms of Action, and Structural Features (A Review)

Abstract The Orthopoxvirus genus (smallpox, monkeypox, etc.) remains a serious threat in the context of the cessation of mass vaccination. This review systematizes data from 2012–2025 on low-molecular-weight orthopoxvirus inhibitors, focusing on their targets and mechanisms of action. Licensed drugs (tecovirimat, cidofovir, brincidofovir) and promising compounds (NIOCH-14) are discussed. Particular attention is paid to new targets: viral replication proteins (D4, E9), transcription factors (F10), enzymes (I7L protease, resolvase, decapping ribonuclease D9), as well as cellular targets (DHODH, SAH hydrolase, BTK and PLK1 kinases). Key structural classes of inhibitors are analyzed: nucleoside analogs, monoterpenoid derivatives (camphor, fenchone), adamantane-based compounds, and heterocyclic systems. The shift from empirical screening to targeted design based on target structures is emphasized. The conclusion highlights significant progress in expanding the arsenal of targets and the chemical diversity of compounds, opening new avenues for developing effective therapies.