Identification of tanshinone I as cap-dependent endonuclease inhibitor with broad-spectrum antiviral effect

The cap-snatching mechanism mediated by cap-dependent endonuclease, which is common among the negative-stranded, segmented RNA viruses in Orthomyxoviridae, Bunyaviridae, and Arenaviridae, is crucial for viral transcription and replication and is thus an attractive target for antiviral drug development. Herein, tanshinone I and its analog tanshinone IIA were identified as candidate compounds with broad-spectrum antiviral activities against bandaviruses, including severe fever with thrombocytopenia syndrome virus, Heartland virus, and Guertu virus. Additionally, the broad-spectrum antiviral activity was observed in influenza A virus and arenavirus. Further study demonstrated that tanshinone I exhibited potent antiviral activity in vitro and significantly reduced the viral loads in vivo. The underlying mechanism was speculated to involve tanshinone I binding to the active pocket of the L protein endonuclease domain to inhibit cap cleavage. This study reports candidate broad-spectrum antiviral compounds against negative-stranded, segmented RNA viruses, highlighting the endonuclease involved in the cap-snatching process as a reliable antiviral target for discovering broad-spectrum antivirals.