Small molecules antiviral drugs have demonstrated their efficiency against a number of viruses. They are available for the treatment of infections with herpes viruses, HIV, HBV, HCV as well as with influenza viruses. Yet for many other emerging and/or neglected viruses causing life-threatening infections there are no drugs available. Ideally, potent and broad-spectrum (i.e. pan-genus or pan family virus activity) antiviral drugs should be developed whereby one drug could be used for the treatment of a number of such viral infections. This proposal will address this goal taking advantage of two recent breakthroughs: 1. The viral cap methyltransferase (MTase) is a newly identified therapeutic target for antiviral treatments, 2. We have developed a new strategy to screen inhibitors of its activity. This new concept in antiviral discovery will be the first step in organizing a task force in emerging viruses management. Partner 2 is the French leader in chemical libraries management and a recognized expert in medicinal chemistry. The development of chemical libraries with added value against identified viral target is the missing key tool for the identification of antivirals targeting the viral MTase. Partner 1 combines an expertise in enzymology of viral enzymes and in developing new approaches in screening. Partner 3 and 4 are internationally recognized for their clinical isolates viruses collection and potential in the evaluation of inhibitors in BSL3/4 environment. This consortium responds to the dual aspect of the ASTRID call, military and civilian purposes and to the DGA POS (Politique et Objectifs Scientifiques). Our strategy is based on the selection of clinically relevant viruses: 1) which represent a threat to exposed humans, 2) from two different Flaviviruses, and Filovirus virus families. Furthermore, the MTase target has never been challenged to that extent, as there was not the possibility to screen against it. This target represents a new opportunity because not only its inhibition will hamper the replication potential of the virus but it will allow the immune system to fight the infection as the viral genome will be unmasked. Then, based on the results of the screening against the enzymes and the clinical isolates, the consortium will demonstrated the proof of concept that targeting MTases have applications in the antiviral fields. The second aim of the proposal is to validate hits and to propose first structure-activity relationship. Our expertise in antiviral development (partner 1 and 3) prompt us in establishing an iterative development with 3 key skills: A-enzyme kinetics/ B-clinical isolates/C-medicinal chemistry, which concern in our consortium A-partner 1/B-partners 3 and 4/C-partner 2. The results arising from these studies are expected to contribute to the development of anti-Flaviviruses, and anti-Filovirus drugs that could prevent and/or treat infection in exposed populations, such as people living nearby an infected livestock or members of the French army and emergency teams that should be present in highly endemic regions for strategic (i.e. military, economical, emergency etc..) reasons.