SUMMARY Coronaviruses, including SARS-CoV-2, pose obvious and imminent dangers to public health. This CAMPP proposal develops compounds that target multiple coronaviruses proteins and replication processes. These proteins include well established drug targets such as protease (Project 1) and replicase (Project 2), and as well as higher risk targets (Project 4). Project 3 – Targeting Druggable Coronavirus Proteins focuses on four less established viral processes that nonetheless have been successfully targeted in at least one proof-of-principle example. These include the coronaviral helicase nsp13 (Aim 1, led by Sumit Chandra at Scripps Research), the nucleocapsid (N) protein, which packages the RNA genome and associates with the budding virion (Aim 2, led by Suganya Selvarajah at Prosetta), the E protein, which encodes an ion channel whose activity likely contributes to virion assembly (Aim 3, led by John Guatelli from UCSD), and the spike (S) protein with mediates fusion of the viral and cellular membranes (Aim 4, lead by Michael Farzan at Scripps Florida). These four targets afford four parallel “shots on goal”. In each case, the lead laboratory has identified novel proof-of-principle chemical matter inhibiting the activity of each protein. These compounds are developed through a common pipeline, and in parallel each aim pursues a custom high-throughput screen designed to address the challenges unique to each target. In the later years of the proposal developmental resources are allocated to the most promising compounds. The overall structure of this proposal is thus designed to maximize the chance of developing an effective inhibitor or coronavirus replication.