Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19
Carmen Mirabelli, Jesse W Wotring, Charles J Zhang, Sean M Mccarty, Reid Fursmidt, Carla D Pretto, Yuanyuan Qiao, Yuping Zhang, Tristan Frum, Namrata S Kadambi, Anya T Amin, Teresa R O'meara, Jason R Spence, Jessie Huang, Konstantinos D Alysandratos, Darrell N Kotton, Samuel K Handelman, Christiane E Wobus, Kevin J Weatherwax, George A Mashour, Matthew J O'meara, Arul M Chinnaiyan, Jonathan Z Sexton
doi:10.1073/pnas.2105815118/-/DCSupplemental
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 identified and translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10 to 15 y from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 US Food and Drug Administration (FDA)-approved compounds and clinical candidates, we identified 17 hits that inhibited SARS-CoV-2 infection and analyzed their antiviral activity across multiple cell lines, including lymph node carcinoma of the prostate (LNCaP) cells and a physiologically relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/ Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infection in vitro. Notably, we discovered that lactoferrin, a glycoprotein found in secretory fluids including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19. SARS-CoV-2 | drug repurposing screening | COVID-19 | lactoferrin S evere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped, positive-sense, single-stranded RNA betacoronavirus that emerged in Wuhan, China in November 2019 and rapidly developed into a global pandemic. The associated disease, COVID-19, manifests with an array of symptoms, ranging from flu-like illness and gastrointestinal distress (1, 2) to acute respiratory distress syndrome, heart arrhythmias, strokes, and death (3, 4). Recently, the US Food and Drug Administration (FDA) issued emergency approval of remdesivir, a nucleoside inhibitor prodrug developed for Ebola virus treatment (5). Although large-scale vaccination is ongoing worldwide, the need for safe, readily available antivirals is still a clinical priority. An antiviral compound that curbs infection and reduces COVID-19 symptoms would be highly useful to control local outbreaks or for home-based management, to protect immunocompromised patients for whom vaccination strategies are not suitable, and to slow the spread of variants of concern that could escape vaccine neutralization. Repurposing of FDA-approved drugs is a promising strategy for identifying rapidly deployable treatments for COVID-19. Benefits of repurposing include known safety profiles, robust supply
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