ABSTRACT
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 Statement
The authors have declared no competing interest.
Footnotes
Conflicts of interest, Jonathan Sexton is the co-founder of Verge Therapeutics, Inc. and owner of Curl Bio, LLC.
Abbreviations
- MOI
- multiplicity of infection
- UMAP
- uniform manifold approximation and projection
- COVID-19
- Coronavirus Disease-2019
- MOA
- mechanism of action
- ROI
- region of interest
- iAEC2
- induced pluripotent stem cell (iPSC)-derived alveolar epithelial type 2 cells
- HCQ
- hydroxychloroquine