Identification of cap-dependent endonuclease inhibitors with broad-spectrum activity against bunyaviruses

Significance Bunyaviruses, like influenza viruses, possess a cap-dependent endonuclease (CEN) that mediates the critical cap-snatching step of viral RNA transcription. We identified the antibunyavirus compounds among influenza CEN inhibitors and identified specific structures involved in the inhibitory mechanism. These were 100- to 1,000-fold more active in vitro than ribavirin against bunyaviruses, including Lassa virus, lymphocytic choriomeningitis virus (LCMV), and Junin virus. In LCMV-infected mice, the compounds significantly decreased blood viral load, suppressed symptoms such as thrombocytopenia and hepatic dysfunction, and improved survival rates. Since effective compounds against other bunyaviruses including La Crosse virus, severe fever with thrombocytopenia syndrome virus, and hantavirus were also identified, we demonstrated the potential clinical utility of CEN inhibitors for the treatment of viral hemorrhagic diseases.