Image based subcellular mapping of the protein landscape of SARS-CoV-2 infected cells for target-centric drug repurposing

The COVID-19 pandemic has resulted in millions of deaths and affected socioeconomic structure worldwide and the search for new antivirals and treatments are still ongoing. In the search for new drug targets and to increase our understanding of the disease, we applied large-scale immunofluorescence profiling to explore host cell response to SARS-CoV-2 infection. Among the 602 host proteins studied in this host response profiling, changes in abundance and subcellular localization were observed for 97 proteins, with 45 proteins showing increased abundance and 10 reduced abundance. 20 proteins displayed changed localization upon infection and an additional 22 proteins displayed altered abundance and localization, together contributing to diverse reshuffling of the host cell protein landscape during infection. We then selected existing and approved small-molecule drugs (n = 123) against our identified host response proteins and identified one compound - elesclomol, that significantly reduced antiviral activity. Our study introduces a novel, targeted and systematic approach based on host protein profiling, to identify new targets for drug repurposing. The dataset of > 100,000 immunofluorescence images from this study are published as a resource available for further studies. AUTHOR SUMMARY: In this study we have evaluated a new approach for identifying drugs that could be used as antiviral drugs, in this case demonstrated for SARS CoV-2. By mining the literature for reported interactions between SARS CoV-2 viral components and host cell proteins, we identified a few hundred host proteins suggested to interact with the virus upon infection. To explore these viral-host interaction proteins further, we developed an image based assay using immunofluorescence and confocal microscopy to visualize the host proteins within infected and non infected cells. This was possible due to the proteome wide collection of antibodies generated within the Human Protein Atlas project, with the aim to systematically map the human proteome in cells and across tissues. The host proteins that altered their location or abundance level upon infection were regarded as putative targets for drug repurposing and we subsequently tested 123 drugs that were targeting a subset of these host proteins. Applying these drugs on two different cell types infected with SARS-CoV-2, revealed a non toxic antiviral effect for one compound that can be explored further as a treatment regimen for SARS-CoV-2 infection. The approach is novel since it combines a targeted approach for drug repurposing screening, giving insight into mechanism of action from start. As such it has the potential to accelerate drug repurposing or identification of targets for new drugs.