Our ultimate goal is to develop novel small molecule, broad-spectrum therapeutics against viral infections caused by filoviruses, arenaviruses, rhabdoviruses, and others that depend on the PPxY L-domain motif for virus egress and spread of infection. Some of these viruses, including Ebola (EBOV), Marburg (MARV), and Lassa fever (LAFV) viruses, are highly pathogenic and classified as Category A, bioterror pathogens. Importantly, we have identified an analog capable of blocking in vivo activity in a Marburg virus challenged mouse model, providing essential proof of concept for this novel class of anti-viral therapeutics. We predict that the novel class of anti-viral products targeting EBOV, MARV, and LAFV will be used for treatment of infected individuals as well as in prophylactic treatment of soldiers, healthcare workers, or others at high risk. Emergency administration of such an antiviral therapeutic during an outbreak could potentially inhibit virus dissemination in infected individuals.