The aim of our project is to develop up to regulatory preclinical level a drug candidate with broad-spectrum inhibitory activities against intracellular toxins and pathogens (viruses, intracellular bacteria and parasites). A realistic approach imposes pharmaceutic development of the drug candidate for a single medical indication. This indication will be the prevention of the Hemolytic Uremic Syndrome (HUS), the complication of infections by Shigatoxin-producing entero-hemorrhagic Escherichia coli (health crisis Hamburg 2011). However, a series of smaller work-packages will enable to strengthen the in vivo efficacy proof of concept of our treatment against other bacterial and viral life threatening infectious diseases responsible in the past and potentially in the future for major bio-threat health crisis. We have discovered and optimized the molecule Retro-2.1, an inhibitor of the transport of toxins and intracellular pathogens from early endosomes to the trans-Golgi network. This molecule is active in the nanomolar range, a concentration suitable for drug development. It is remarkably non-toxic in mice. In collaboration with the members of our network, demonstration of efficacy of the hit molecule Retro-2 (precursor of Retro-2.1) was done in mice models of ricin intoxication, Shiga toxin-producing E. coli O104:H4, Leishmania parasite, poxviruses and enterovirus 71. In vitro data showing a strong level of protection of cells by Retro-2.1 was observed for Ebola and Marburg viruses, Chlamydia trachomatis responsible for eye and sexually transmitted infections, Francisella tularensis a rare but extremely deadly bacteria, and other viruses. Recent work enabled to formulate Retro-2.1 for intravenous administration, the preferred route of treatment for many of the targeted diseases listed above during which the health condition restricts oral administration (nausea, vomiting, diarrhea…). Pharmacokinetics measures were performed. The next steps, aim of the proposal, are to assess for the formulated Retro-2.1: - Structure of interaction with its molecular target - Full pharmacokinetics and biodistribution in mouse and a large animal (dog or monkey) - Full absorption, metabolism and excretion in mouse and a large animal - Non-regulatory and regulatory toxicology in mouse and a large animal - In vivo dose efficacy in mouse against our primary targeted disease, Shigatoxin-producing E. coli strains O157:H7 and O104:H4. - In vivo efficacy in mouse against our secondary targeted diseases: Ebola virus, poxviruses, enterovirus 71, Chlamydia trachomatis, Francisella tularensis. European society is extremely vulnerable to internal, imported or global infectious health crisis. Emerging infectious diseases raise exponentially from year to year. Currently, more than 100 outbreaks occur each year, some with devastating human and economic impacts. Thus there is a need for broad-spectrum therapies that could be efficient on endemic, rare or even unknown pathogens because development of new agent-specific drugs is too long (>10 years) and costly (25 M€<<300 M€). Such drugs must reduce the risks of resistanceacquisition by the pathogens. Although not fully demonstrated, many experts consider that drugs targeting the host rather than the pathogen may reduce the risk of resistance. This is precisely how our drug candidate is designed. It targets a component of the intracellular trafficking machinery that is exploited by intracellular pathogens and thus protects the host rather than kills the pathogens.