INHIBITORS OF BUNYAVIRIDAE AND USES THEREOF

Humans can be infected by Rift Valley Fever Virus (RVFV) via contact with infected animal body fluids or tissues, by breathing aerosols contaminated with RVFV, or less frequently via mosquito bites. 8-10% of infections are severe, where symptoms can include lesions to the eye causing blindness in 50% of ocular cases (1-10% of all infections), encephalitis, gastrointestinal dysfunction, jaundice, joint/muscle pain, hemorrhagic fever, disorientation/hallucination, and partial paralysis. Hemorrhagic fever is rare but has a ~50% fatality rate. There is no vaccine for RVFV in humans. RVFV and Crimean-Congo Hemorrhagic Fever Virus (CCHFV) are among the emerging viral pathogens for which there are insufficient or inadequate medical treatments, or pipelines to develop them, that were highlighted in the 2018 World Health Organization research and development blueprint for high priority targets. Both RVFV and CCHFV are listed by the American government as select agents of significant concern as biowarfare threats. Rift Valley fever virus (RVFV, Bunyavirales) is a veterinary and human pathogen and is an agent of bioterrorism concern. The present invention concerns 47 novel RVFV inhibitors with selective indexes from 1.1 – 103 and 50% effective concentrations of 1.2 – 56 µM in Vero cells, primarily α-Hydroxytropolones and N-Hydroxypyridinediones. Inhibitor activity and the selective index were validated in the human cell line A549. To evaluate specificity, select compounds were tested against a second Bunyavirus, La Crosse Virus (LACV), and the flavivirus Zika (ZIKV). Our data indicate that the α-Hydroxytropolone and N-Hydroxypyridinedione chemotypes can also be active against related pathogens, including Hantaan virus, severe fever with thrombocytopenia syndrome virus, Crimean-Congo hemorrhagic fever virus.