The family Bunyaviridae is comprised of a diverse group of viruses spread across five genera and infecting hosts from both the plant and animal kingdoms. Significant biothreats among these are several human pathogens including Rift Valley fever virus (RVFV), Crimean-Congo hemorrhagic fever virus (CCHF), hantavirus, and La Crosse encephalitis virus (LACV). A broad-spectrum bunyavirus antiviral would have great utility against natural or intentional introduction of these agents into population centers, as well as provide a treatment option in areas where these pathogens are endemic. The goal of the SIGA Bunyavirus product development program described here is to develop a broad-spectrum, small-molecule therapeutic for the treatment and prevention of disease caused by RVFV, a Category A priority pathogen, and LACV, a ategory B pathogen. Using sensitive high-throughput screens developed for both LACV and RVFV, we have identified several candidate compounds (quality hits) with broad-spectrum antiviral properties against these related pathogens from among the 206,000 small molecules in the SIGA chemical compound library. This dual screening strategy has also allowed identification of nontoxic compounds with antiviral activities that extend beyond the family Bunyaviridae against viruses in the Poxviridae, Togaviridae, and Flaviviridae families, presumably by targeting host pathways essential for replication of a diversity of virus families. Lead series will be assessed with respect to mechanism of action, metabolic stability, pharmacokinetic properties, and efficacy in small animal models of bunyavirus disease in an effort to obtain data necessary for the submission of an application for an Investigational New Drug (IND). RELEVANCE (See instructions): To date, there are no specific vaccines or antivirals approved for the treatment of the Category A, B, or C bunyavirus infections in humans.Of note is the presence of four different members of the family Bunyaviridae among the viruses characterized as biothreats to the United States. The development of a broad-spectrum antiviral treatment for bunyavirus infection is the primary goal of the work outlined in this proposal.