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Developing High Affinity Peptides to Target SARS-CoV-2 Spike (S) Protein

There is a pressing need for new diagnostic and therapeutic tools to address the worldwide COVID-19 pandemic. Regarding diagnostics, robust new tools are needed to detect SARS-CoV-2 antigens (e.g., spike protein (S)) to enable sensitive, rapid, point-of- care monitoring of infections. Sensitive antigen tests are important because they provide a direct route to identify asymptomatic and pre-symptomatic individuals. Regarding therapeutics, there are currently no approved virus-directed therapeutics that prevent infection or lessen the severity of infections. The interaction between the virus S protein and its cell-surface receptor (angiotensin converting enzyme 2 = ACE2) is essential for infection. High affinity peptides that block virus S protein may therefore be potent SARS-CoV-2 neutralizing agents. This proposal aims to develop novel peptide ligands directed at SARS-CoV-2 spike (S) protein toward the goal of creating COVID-19 therapeutics and diagnostics. To do this, we will use mRNA display directed evolution experiments to screen trillion member peptide libraries based on ACE2. We propose two specific aims: Aim 1: mRNA display selections targeting SARS-CoV-2 S protein receptor binding domain. Aim 2: Biochemical characterization of our SARS-CoV-2 S selected peptides. If we are successful, the peptides we develop will represent new patentable compositions of matter for use as sensitive diagnostic tools and leads for readily constructed virus neutralizing agents. This approach may also provide a general route to develop tools for future coronaviruses.