Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19.

Animals Antiviral Agents / pharmacology COVID-19 / immunology Caco-2 Cells Cell Line, Tumor Chlorocebus aethiops Dose-Response Relationship, Drug Drug Discovery Drug Repositioning / methods Epithelial Cells Heparitin Sulfate / antagonists & inhibitors Hepatocytes High-Throughput Screening Assays Humans Immunologic Factors / pharmacology Lactoferrin / pharmacology SARS-CoV-2 / drug effects Vero Cells Virus Internalization / drug effects Virus Replication / drug effects COVID-19 Drug Treatment
COVID-19 SARS-CoV-2 drug repurposing screening lactoferrin

Journal

Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876

Informations de publication

Date de publication:
07 09 2021
Historique:
entrez: 20 8 2021
pubmed: 21 8 2021
medline: 1 9 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1073/pnas.2105815118 PMID: 34413211 PMC: PMC8433531
pubmed: 34413211
pii: 2105815118
doi: 10.1073/pnas.2105815118
pmc: PMC8433531
pii:
doi:

Substances chimiques

Antiviral Agents 0
Immunologic Factors 0
Heparitin Sulfate 9050-30-0
Lactoferrin EC 3.4.21.-

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : NHLBI NIH HHS
ID : R01 HL119215
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA046592
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI116482
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK089503
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK120623
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002240
Pays : United States
Organisme : NIDCR NIH HHS
ID : T32 DE007057
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA231996
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007767
Pays : United States

Commentaires et corrections

Type : UpdateOf

Informations de copyright

Copyright © 2021 the Author(s). Published by PNAS.

Déclaration de conflit d'intérêts

The authors declare no competing interest.

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Auteurs

Carmen Mirabelli (C)

Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109.

Jesse W Wotring (JW)

Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109.
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109.

Charles J Zhang (CJ)

Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109.
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109.

Sean M McCarty (SM)

Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109.

Reid Fursmidt (R)

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109.
Center for Drug Repurposing, University of Michigan, Ann Arbor, MI 48109.

Carla D Pretto (CD)

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109.

Yuanyuan Qiao (Y)

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109.
Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
ORCID: 0000-0002-1178-3480

Yuping Zhang (Y)

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109.
Department of Pathology, University of Michigan, Ann Arbor, MI 48109.

Tristan Frum (T)

Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109.

Namrata S Kadambi (NS)

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109.

Anya T Amin (AT)

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109.

Teresa R O'Meara (TR)

Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109.

Jason R Spence (JR)

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109.
Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109.

Jessie Huang (J)

Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118.
Pulmonary Center, Boston University School of Medicine, Boston, MA 02118.
Department of Medicine, Boston University School of Medicine, Boston, MA 02118.
ORCID: 0000-0002-5297-3563

Konstantinos D Alysandratos (KD)

Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118.
Pulmonary Center, Boston University School of Medicine, Boston, MA 02118.
Department of Medicine, Boston University School of Medicine, Boston, MA 02118.

Darrell N Kotton (DN)

Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118.
Pulmonary Center, Boston University School of Medicine, Boston, MA 02118.
Department of Medicine, Boston University School of Medicine, Boston, MA 02118.

Samuel K Handelman (SK)

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109.
Center for Drug Repurposing, University of Michigan, Ann Arbor, MI 48109.

Christiane E Wobus (CE)

Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109.
ORCID: 0000-0001-5286-0924

Kevin J Weatherwax (KJ)

Center for Drug Repurposing, University of Michigan, Ann Arbor, MI 48109.
Michigan Institute for Clinical and Health Research, University of Michigan, Ann Arbor, MI 48109.
College of Pharmacy, University of Michigan, Ann Arbor, MI 48109.

George A Mashour (GA)

Center for Drug Repurposing, University of Michigan, Ann Arbor, MI 48109.
Michigan Institute for Clinical and Health Research, University of Michigan, Ann Arbor, MI 48109.
Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109.

Matthew J O'Meara (MJ)

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109.

Arul M Chinnaiyan (AM)

Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109; arul@umich.edu jzsexton@med.umich.edu.
Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109.
HHMI, University of Michigan, Ann Arbor, MI 48109.
Department of Urology, University of Michigan, Ann Arbor, MI 48109.

Jonathan Z Sexton (JZ)

Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109; arul@umich.edu jzsexton@med.umich.edu.
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109.
Center for Drug Repurposing, University of Michigan, Ann Arbor, MI 48109.
Michigan Institute for Clinical and Health Research, University of Michigan, Ann Arbor, MI 48109.

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