Abstract The Medicinal Chemistry Core (MCC; Core 4) has been formed to address the urgent need for novel antiviral agents. The MCC will work seamlessly with the Project Teams and other Cores to drive the time- and cost- efficient discovery and development of novel optimized lead compounds to target viral infections of global health significance. Critical to its mission is its competence in industrial and academic medicinal chemistry, which is highlighted by successful evolutions of hit to lead to approved drug. The MCC will aid in the confirmation of hits discovered through structure-based design or experimental screens, evolve these to early and then optimized leads following a defined workflow with quantitative metrics for molecules at each stage in the process. The MCC will collaborate on projects focused on the discovery and development of 1) inhibitors of SARS-CoV-2 RNA dependent RNA polymerase (RdRp) (Nsp12/7/8) and exonuclease (ExoN) (Nsp14/10), 2) viral protease inhibitors from a high-throughput yeast-based screen, and 3) syn-BNP peptides as antiviral agents.