Exploring the morphology of the host cell to open new possibilities for drug repurposing in viral infections

New approaches are needed to identify novel or repurposed drugs to treat deadly viral infections. Majority of screening methods evaluate the drug activity on a given virus while neglecting the host mechanisms and responses to the virus infection.Here, we investigate antiviral activity of 5200 compounds from the SPECS drug repurposing library by three distinct screening campaigns: 1) host cell morphology changes by phenomics assay Cell Painting 2) antibody-detection of SARS-CoV-2infection and 3) the gold-standard cytopathic effect method. We demonstrate how SARS-CoV-2 infection induced a specific phenotypic signature in Vero E6 cells, which was reversed by assay controls such as remdesivir. Our unbiased host-focused approach identified additional 324 compounds with antiviral activity against SARS-CoV-2.

To further study 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 host proteins 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 for the discovery of antivirals and could be applied for other emerging or re-emerging viruses.