Abstract

The continued threat by emerging viruses to humankind has highlighted the need for new approaches to identify novel or repurposed drugs. Currently, the majority of antiviral screening methods evaluate the drug activity on a given virus and neglect the host mechanisms that the virus hijacks. To include host cell morphology changes in antiviral screening we combined morphological profiling using the Cell Painting assay with antibody-detection of viral infection and screened 5144 compounds in the SPECS drug repurposing library. SARS-CoV-2 infection induced a virus-specific phenotypic signature in Vero E6 cells, which was reversed by assay controls such as remdesivir. Our unbiased host-focused approach identified additional ~70 compounds that were able to revert SARS-CoV-2 infected host cells towards a healthy cell phenotype. To further deepen our understanding on the host response during infection, we quantified the subcellular localization and expression of 602 host proteins using antibodies from the Human Protein Atlas. We identified phenotypic responses to SARS-CoV-2 infection in 97 proteins. Finally, to broaden the paradigm of how antiviral therapies are identified we aim to  combine these host focused screening approaches. Our preliminary analyses have identified 3 potential drug targets linked to 3 compounds that reverse the virus-specific phenotype, which all represent novel drug repurposing candidates against SARS-CoV-2. Taken together, these findings illustrate a new host-centric approach to discovery antivirals and could be applied for other emerging or re-emerging viruses