The scope of this proposal is to contribute to the identification of antivirals against SARS-CoV-2, which unfortunately does not need to be described. Antivirals, because highly potent and safe direct-acting antiviral drugs are available for the treatment of a number of chronic viral infections such as, of course, HIV (~30 approved drugs, used in effective combinations) but also against hepatitis C virus (HCV). Powerful and specifically developed antiviral drugs have been shown to help solve, and potentially cure, virus-induced diseases. This requires integrated approaches involving cheminformatics specialists, HTS experts, biochemists and virologists working on enzyme purification and infected cells, both in pathways and animal models. The Antiviral Drug Design Platform (AD2P) is an IBiSA/ChemBioFrance labeled platform with a long-lasting experience of successful collaborations, both nationally and internationally. Based in Marseille, it gives us the opportunity to work actively together, without being limited by logistical obligations. It should be noted that such an approach has already been performed on the SARS-CoV-1, including screening of many standard chemical libraries. To go further, new chemical libraries should be used to broaden the scope of the chemical space of currently available drugs. We have shown that the CoV-SARS replication complex requires three proteins: nsp7, nsp8 and nsp12. Disruption of this complex with chemical molecules selected to inhibit Protein-Protein Interaction (‘PPI-like inhibitors’) has never been reported. We have such a chemical library available in France, ‘Fr-PPIChem’, thanks to a national consortium financed by the ANR (#ANR-15-CE18-0023 coordinated by X Morelli, partner 3 of the current grant application). The bioassay is based on the inhibition of the activity of the replication complex. Described at the test tube level, we are in the process of scaling up the production/purification of the necessary proteins to develop a non-radioactive test and to miniaturize the test to adapt it to High Thoughput Screening (HTS): our platform will be ready to start screening very soon. It should be noted that this has never been done before for Coronavirus. Screening results will be analyzed, then structural analogs of the hits will be selected in commercially-available libraries and purchased. They will be evaluated in vitro and the best compounds will be tested on infected cells. In the search for analogs, existing drugs will be included. Once iterative work has been carried out, through screening, IC50s determination, biophysical determination and bioinformatics analyses, the most potent molecule(s) will be evaluated in a small animal model that will have been set up in the meanwhile. The expected support of ANR is to: - Set up an HTS assay based on the replication complex of SARS-CoV, a breakthrough - Broaden the chemical space to identify antivirals, a disruptive mean - Set up screening assays on cells infected with potentially different strains of SARS-CoV2, on different cell lines - Set up an animal model to evaluate the potential of selected molecules. In conclusion, we need the support of the ANR to achieve these objectives and conceive unique tools that will be made available to the research community, while at the same time dealing with antivirals, broadening the scope of the chemical space.