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. IMPORTANCE: The spread of avian-borne, tick-borne, and rodent-borne pathogens has the potential to pose a serious threat to human health, and candidate vaccines as well as therapeutics for these pathogens are urgently needed. Tanshinones, especially tanshinone I, were identified as a cap-dependent endonuclease inhibitor with broad-spectrum antiviral effects on negative-stranded, segmented RNA viruses including bandavirus, orthomyxovirus, and arenavirus from natural products, implying an important resource of candidate antivirals from the traditional Chinese medicines. This study supplies novel candidate antivirals for the negative-stranded, segmented RNA virus and highlights the endonuclease involved in the cap-snatching process as a reliable broad-spectrum antiviral target.