Discovery of a ligandable host antiviral target by chemical proteomics 4740

Abstract Description Emerging infectious diseases are a significant threat to global health, as evidenced by the SARS-CoV-2 pandemic. Although the deployment of vaccines has mitigated the risk of severe COVID-19 disease, the continuous threat of SARS-CoV-2 variants can compromise vaccine efficacy and emphasizes the need for alternative therapeutic strategies. Strategies to identify host factors important for viral infection have included functional genomic screens and biochemical methods although these approaches have limitations and do not yield corresponding chemical probes to study identified proteins. Using a library of stereochemically-defined compounds (photo-stereoprobes) that contain a diazirine and an alkyne handle for covalent UV-crosslinking and click chemistry enrichment of liganded proteins, we identify a set of probes that inhibit SARS-CoV-2. Through integrated phenotypic screens and proteomics-based target identification, we find that the active photo-stereoprobes ligand the host translational protein ETF1. Mechanistic studies reveal that the photo-stereoprobes modulate the highly regulated ribosomal frameshifting mechanism utilized by multiple viruses. Perturbation of this mechanism with the photo-stereoprobes modulated the infectivity level of viruses that utilize the frameshifting mechanism. Our findings show how the use of stereochemically-defined compounds in phenotypic screens can identify druggable host targets to combat SARS-CoV-2 and potentially other emerging viruses. Funding Sources ASK was supported in part by Open Philanthropy and the Life Sciences Research Foundation Topic Categories Viral Immunology (VIR)