Project Summary The pandemic COVID-19 has, as of April 13, 2020, infected nearly 2M individuals worldwide, with over 560,000 U.S. cases and over 22,000 U.S. deaths. There are no FDA approved vaccines or treatments for COVID-19. This supplemental proposal describes the accelerated development of such a drug, with potential near-term uses of these early therapeutic candidates for probing the structural-function relationships between the SARS-CoV-2 spike protein and the human ACE2 receptor protein. This work builds directly from Project 2 of the NCI-supported U54 NSBCC program. The specific aims of that project center around the technology of Protein Catalyzed Capture agents (PCCs),1 with a specific focus on developing technologies for the high-through production of PCCs, as well as an emphasis on drug-targeting the KRASG12D oncoprotein. A unique aspect of PCCs is that they are, by design, developed to bind to a specific epitope on a specific protein,2 thus providing an avenue for targeting an epitope containing a genetic mutation (relevant to oncoproteins),3 or providing an avenue for targeting epitopes that are broadly conserved, which bears relevance to targeting strategies aimed at the SARS- CoV-2 coronavirus. That NSBCC-funded project has proceeded well (with progress towards KRASG12D-specific inhibitors recently attracting additional investments). Further, we have also recently shown, using other funding, that the platform can be harnessed to selectively target antibiotic resistance pathogens using a variant of the PCC technology termed antibody-recruiting(AR) PCCs.4 Here we seek to combine the high-throughput aspect of PCC development that has been supported by the NCI,5 with the pathogen-targeting approach, to develop a series of precisely targeted inhibitors against SARS-CoV-2. This work has already been moving forward for the past few weeks, and is nearing the point where animal model work will soon be required.