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Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19
Mirabelli et al., Proceedings of the National Academy of Sciences, doi:10.1073/pnas.2105815118 (In Vitro)
Mirabelli et al., Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19, Proceedings of the National Academy of Sciences, doi:10.1073/pnas.2105815118 (In Vitro)
Aug 2021   Source   PDF  
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In Vitro study testing 1,425 compounds for SARS-CoV-2 antiviral activity, identifying 17 dose-responsive compounds with IC50 values <1μM. Lactoferrin inhibited SARS-CoV-2 in the nanomolar range in all cell models with multiple modes of action.
5 In Vitro studies support the efficacy of lactoferrin [Cutone, Mirabelli, Ostrov, Piacentini, Salaris].
Mirabelli et al., 19 Aug 2021, peer-reviewed, 23 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
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Abstract: Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19 Carmen Mirabellia,1, Jesse W. Wotringb,c,1, Charles J. Zhangb,c,2, Sean M. McCartyb,2, Reid Fursmidtc,d,2, Carla D. Prettoc, Yuanyuan Qiaoe,f, Yuping Zhange,f, Tristan Frumg, Namrata S. Kadambic, Anya T. Aminc, Teresa R. O’Mearaa, Jason R. Spencec,g, Jessie Huangh,i,j, Konstantinos D. Alysandratosh,i,j, Darrell N. Kottonh,i,j, Samuel K. Handelmanc,d, Christiane E. Wobusa, Kevin J. Weatherwaxd,k,l, George A. Mashourd,k,m, Matthew J. O’Mearan,3, Arul M. Chinnaiyane,f,o,p,q,3,4, and Jonathan Z. Sextonb,c,d,k,3,4 a Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; bDepartment of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109; cDepartment of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109; dCenter for Drug Repurposing, University of Michigan, Ann Arbor, MI 48109; eMichigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109; fDepartment of Pathology, University of Michigan, Ann Arbor, MI 48109; g Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109; hCenter for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118; iPulmonary Center, Boston University School of Medicine, Boston, MA 02118; jDepartment of Medicine, Boston University School of Medicine, Boston, MA 02118; kMichigan Institute for Clinical and Health Research, University of Michigan, Ann Arbor, MI 48109; l College of Pharmacy, University of Michigan, Ann Arbor, MI 48109; mDepartment of Anesthesiology, University of Michigan, Ann Arbor, MI 48109; n Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109; oRogel Cancer Center, University of Michigan, Ann Arbor, MI 48109; pHHMI, University of Michigan, Ann Arbor, MI 48109; and qDepartment of Urology, University of Michigan, Ann Arbor, MI 48109 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..
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