Your browser doesn't support javascript.
Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19.
Mirabelli, Carmen; Wotring, Jesse W; Zhang, Charles J; McCarty, Sean M; Fursmidt, Reid; Pretto, Carla D; Qiao, Yuanyuan; Zhang, Yuping; Frum, Tristan; Kadambi, Namrata S; Amin, Anya T; O'Meara, Teresa R; Spence, Jason R; Huang, Jessie; Alysandratos, Konstantinos D; Kotton, Darrell N; Handelman, Samuel K; Wobus, Christiane E; Weatherwax, Kevin J; Mashour, George A; O'Meara, Matthew J; Chinnaiyan, Arul M; Sexton, Jonathan Z.
  • Mirabelli C; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109.
  • Wotring JW; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109.
  • Zhang CJ; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109.
  • McCarty SM; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109.
  • Fursmidt R; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109.
  • Pretto CD; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109.
  • Qiao Y; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109.
  • Zhang Y; Center for Drug Repurposing, University of Michigan, Ann Arbor, MI 48109.
  • Frum T; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109.
  • Kadambi NS; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109.
  • Amin AT; Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
  • O'Meara TR; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109.
  • Spence JR; Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
  • Huang J; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109.
  • Alysandratos KD; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109.
  • Kotton DN; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109.
  • Handelman SK; Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109.
  • Wobus CE; Department of Internal Medicine, Division of Gastroenterology and Hepatology, Michigan Medicine at the University of Michigan, Ann Arbor, MI 48109.
  • Weatherwax KJ; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109.
  • Mashour GA; Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118.
  • O'Meara MJ; Pulmonary Center, Boston University School of Medicine, Boston, MA 02118.
  • Chinnaiyan AM; Department of Medicine, Boston University School of Medicine, Boston, MA 02118.
  • Sexton JZ; Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118.
Proc Natl Acad Sci U S A ; 118(36)2021 09 07.
Article in English | MEDLINE | ID: covidwho-1366851
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 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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Virus Replication / Virus Internalization / SARS-CoV-2 / Immunologic Factors / Lactoferrin Type of study: Prognostic study Limits: Animals / Humans Language: English Year: 2021 Document Type: Article

Similar

MEDLINE

...
LILACS

LIS


Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Virus Replication / Virus Internalization / SARS-CoV-2 / Immunologic Factors / Lactoferrin Type of study: Prognostic study Limits: Animals / Humans Language: English Year: 2021 Document Type: Article