ИСТИНА

BACKGROUND: Plants of the Simaroubaceae family are extensively utilized in traditional oriental medicine. Remedies derived from diverse parts of these plants are known for their antitumor and anti-inflammatory properties, and are also used to combat parasites and viral diseases. The major active components of these preparations are quassinoids, small molecules of the triterpene family, such as ailanthone, bruceantin, eurycumanone, and others. Despite the well-documented therapeutic effects of these compounds, their targets in eukaryotic cells and the molecular mechanism of their action remain poorly understood. METHODS AND RESULTS: In this study we employed mRNA transfection, in vitro translation, and fluorescent toe-printing to demonstrate that quassinoids inhibit protein synthesis in mammalian cells, resulting in translational arrest at the elongation stage. Using high-resolution cryo-electron microscopy, we obtained the structures of the human 80S ribosome in complex with ailanthone and bruceantin, which showed that quassinoids prevent the accommodation of aminoacyl-tRNA in the A-site of the 60S ribosomal subunit. A resolution of 2.1 Å allowed for the detailed examination of the intermolecular contacts of the small molecules with the components of the peptidyl transferase center. We next found that ailanthone inhibited the growth of transformed cell lines and caused cell accumulation in the G0/G1 phase. Though, at lower concentrations, it increased the survival of cultured cells when infected with cytopathic picornaviruses. CONCLUSIONS: We identified protein synthesis as a target for quassinoid activity and elucidated their mechanism of action by obtaining a high-resolution structure of ailanthone and bruceantin on the human ribosome. These findings present promising prospects for the use of quassinoids in clinical applications, specifically for anticancer and antiviral treatments.