Rapid Identification of Druggable Targets and the Power of the PHENotype SIMulator for Effective Drug Repurposing in COVID-19.

The current, rapidly diversifying pandemic has accelerated the need for efficient and effective identification of potential drug candidates for COVID-19. Knowledge on host-immune response to SARS-CoV-2 infection, however, remains limited with very few drugs approved to date. Viable strategies and tools are rapidly arising to address this, especially with repurposing of existing drugs offering significant promise. Here we introduce a systems biology tool, the PHENotype SIMulator, which - by leveraging available transcriptomic and proteomic databases - allows modeling of SARS-CoV-2 infection in host cells in silico to i) determine with high sensitivity and specificity (both > 96%) the viral effects on cellular host-immune response, resulting in a specific cellular SARS-CoV-2 signature and ii) utilize this specific signature to narrow down promising repurposable therapeutic strategies. Powered by this tool, coupled with domain expertise, we have identified several potential COVID-19 drugs including methylprednisolone and metformin, and further discern key cellular SARS-CoV-2-affected pathways as potential new druggable targets in COVID-19 pathogenesis.