Emergence of viral pathogens is a serious public health problem. Some highly pathogenic RNA viruses provoke severe and sometimes fatal human diseases called viral hemorrhagic fevers (VHF). These viruses are of strategic relevance for the French nation. They can potentially emerge in some French territories and affect civilian populations. Furthermore, they are of particular interest for the French army since these pathogens (i) are considered as potential viral bioterrorism agents and (ii) might be present in regions where French troops are deployed. The therapeutics currently used against viruses involved vaccines and antiviral molecules, which have proven to be highly effective in the past. However, the current model of antiviral drug discovery and development is still focused on a given virus, very expensive, and takes a long time to achieve marketing authorization approval. New approaches are therefore needed to address the urgent threats posed by viruses that cause VHF. Indeed, these ‘neglected’ viral pathogens, without clearly identified commercial market cannot take advantage of specific developments at a global scale. This project will therefore aim to unlock these scientific barriers. In order to develop new therapeutics against VHF, the following strategy will be applied: -We will use broad-spectrum antiviral molecules. This strategy will also be potentially advantageous in case of new viral emergence phenomena. -We will use some antiviral molecules already approved in industrialized countries. These drugs will allow for rapid therapeutic proposals to be considered. -Association of two antiviral molecules will be tested. Indeed, a disadvantage of using broad-spectrum molecules is often the need of using high doses to obtain satisfactory antiviral activity. Thus, during this project, a panel of broad-spectrum antiviral molecules with different modes of action will be evaluated on a set of highly pathogenic viruses of the Arenaviridae, Filoviridae and Flaviviridae families and with members of Bunyavirales that cause VHF. Some of these viruses will be manipulated in biosafety level-4 laboratory. The project will take place in three successive stages: -In vitro analysis of each broad-spectrum antiviral compound alone. -In vitro analysis of the best compounds in association two by two in order to find synergetic effects. -In vivo analysis of the best compound associations. A smaller panel of three virus will be use at this stage. The objective of this project is to (i) study systematically in vitro and in vivo activity of broad-spectrum antiviral compounds used alone or in association to find synergetic effects and (ii) to provide at the end one or two associations of broad-spectrum antiviral compounds. In addition, preferably in association with an industrial partner, the development of these therapeutics could subsequently involve a study using non-human primates. This could be the subject of an application for Astrid Maturation funding. Finally, this project will provide a dedicated, structured platform with validated protocols able of characterizing in vitro and in vivo antiviral molecules against highly pathogenic viruses, which could be used in the future by industrial partners or public laboratories.