Morphological Cell Profiling of SARS-CoV-2 Infection Identifies Drug Repurposing Candidates for COVID-19.

Autor:	Mirabelli C; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Wotring JW; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA., Zhang CJ; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA., McCarty SM; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA., Fursmidt R; Department of Internal Medicine, Gastroenterology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA.; U-M Center for Drug Repurposing, University of Michigan, Ann Arbor, MI, 48109, USA., Frum T; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA., Kadambi NS; Department of Internal Medicine, Gastroenterology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA., Amin AT; Department of Internal Medicine, Gastroenterology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA., O'Meara TR; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Pretto CD; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Spence JR; Department of Internal Medicine, Gastroenterology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA.; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA., Huang J; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, 02118, USA.; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA., Alysandratos KD; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, 02118, USA.; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA., Kotton DN; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, 02118, USA.; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA., Handelman SK; Department of Internal Medicine, Gastroenterology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA.; U-M Center for Drug Repurposing, University of Michigan, Ann Arbor, MI, 48109, USA., Wobus CE; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA., Weatherwax KJ; U-M Center for Drug Repurposing, University of Michigan, Ann Arbor, MI, 48109, USA.; Michigan Institute for Clinical and Health Research (MICHR), University of Michigan, Ann Arbor, MI, 48109, USA.; College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA., Mashour GA; U-M Center for Drug Repurposing, University of Michigan, Ann Arbor, MI, 48109, USA.; Michigan Institute for Clinical and Health Research (MICHR), University of Michigan, Ann Arbor, MI, 48109, USA.; Department of Anesthesiology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA., O'Meara MJ; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, 48109, USA., Sexton JZ; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA.; Department of Internal Medicine, Gastroenterology, Michigan Medicine at the University of Michigan, Ann Arbor, MI, 48109, USA.; U-M Center for Drug Repurposing, University of Michigan, Ann Arbor, MI, 48109, USA.; Michigan Institute for Clinical and Health Research (MICHR), University of Michigan, Ann Arbor, MI, 48109, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2020 Dec 07. Date of Electronic Publication: 2020 Dec 07.
DOI:	10.1101/2020.05.27.117184
Abstrakt:	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 10-15 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 agents against SARS-CoV-2. From a library of 1,425 FDA-approved compounds and clinical candidates, we identified 17 dose-responsive compounds with in vitro antiviral efficacy in human liver Huh7 cells and confirmed antiviral efficacy in human colon carcinoma Caco-2, human prostate adenocarcinoma LNCaP, and in a physiologic 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 classically 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. Competing Interests: Conflicts of interest The authors declare no conflicts of interest.
Databáze:	MEDLINE
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