PT - JOURNAL ARTICLE AU - Carmen Mirabelli AU - Jesse W. Wotring AU - Charles J. Zhang AU - Sean M. McCarty AU - Reid Fursmidt AU - Namrata S. Kadambi AU - Anya T. Amin AU - Teresa R. O’Meara AU - Carla D. Pretto AU - Tristan Frum AU - Jason R. Spence AU - Konstantinos D. Alysandratos AU - Jessie Huang AU - Darrell N. Kotton AU - Christiane E. Wobus AU - Kevin J. Weatherwax AU - George A. Mashour AU - Samuel K. Handelman AU - Matthew J. O’Meara AU - Jonathan Z. Sexton TI - Morphological Cell Profiling of SARS-CoV-2 Infection Identifies Drug Repurposing Candidates for COVID-19 AID - 10.1101/2020.05.27.117184 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.05.27.117184 4099 - http://biorxiv.org/content/early/2020/05/27/2020.05.27.117184.short 4100 - http://biorxiv.org/content/early/2020/05/27/2020.05.27.117184.full AB - The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly translated to clinical care. Unfortunately, traditional drug discovery methods have a >90% failure rate and can take 10-15 years from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious single agents and combination therapies against SARS-CoV-2. Quantitative high-content morphological profiling was coupled with an AI-based machine learning strategy to classify features of cells for infection and stress. This assay detected multiple antiviral mechanisms of action (MOA), including inhibition of viral entry, propagation, and modulation of host cellular responses. From a library of 1,441 FDA-approved compounds and clinical candidates, we identified 15 dose-responsive compounds with antiviral effects. In particular, we discovered that lactoferrin is an effective inhibitor of SARS-CoV-2 infection with an IC50 of 308 nM and that it potentiates the efficacy of both remdesivir and hydroxychloroquine. Lactoferrin also stimulates an antiviral host cell response and retains inhibitory activity in iPSC-derived alveolar epithelial cells. Given its safety profile in humans, these data suggest that lactoferrin is a readily translatable therapeutic adjunct for COVID-19. Additionally, several commonly prescribed drugs were found to exacerbate viral infection and warrant clinical investigation. We conclude that morphological profiling for drug repurposing is an effective strategy for the selection and optimization of drugs and drug combinations as viable therapeutic options for COVID-19 pandemic and other emerging infectious diseases.Competing Interest StatementThe authors have declared no competing interest.MOImultiplicity of infectionUMAPuniform manifold approximation and projectionCOVID-19Coronavirus Disease-2019MOAmechanism of actionROIregion of interestiAEC2induced pluripotent stem cell (iPSC)-derived alveolar epithelial type 2 cellsHCQhydroxychloroquine