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Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A.
White, Kris M; Rosales, Romel; Yildiz, Soner; Kehrer, Thomas; Miorin, Lisa; Moreno, Elena; Jangra, Sonia; Uccellini, Melissa B; Rathnasinghe, Raveen; Coughlan, Lynda; Martinez-Romero, Carles; Batra, Jyoti; Rojc, Ajda; Bouhaddou, Mehdi; Fabius, Jacqueline M; Obernier, Kirsten; Dejosez, Marion; Guillén, María José; Losada, Alejandro; Avilés, Pablo; Schotsaert, Michael; Zwaka, Thomas; Vignuzzi, Marco; Shokat, Kevan M; Krogan, Nevan J; García-Sastre, Adolfo.
  • White KM; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. kris.white@mssm.edu nevan.krogan@ucsf.edu adolfo.garcia-sastre@mssm.edu.
  • Rosales R; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Yildiz S; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Kehrer T; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Miorin L; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Moreno E; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Jangra S; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Uccellini MB; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Rathnasinghe R; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Coughlan L; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Martinez-Romero C; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Batra J; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Rojc A; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Bouhaddou M; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Fabius JM; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Obernier K; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Dejosez M; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Guillén MJ; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Losada A; Department of Microbiology and Immunology and Center for Vaccine Development and Global Health (CVD), University of Maryland School of Medicine, Baltimore, MD, USA.
  • Avilés P; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Schotsaert M; Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Zwaka T; Quantitative Biosciences Institute (QBI), University of California, San Francisco, CA 94158, USA.
  • Vignuzzi M; J. David Gladstone Institutes, San Francisco, CA 94158, USA.
  • Shokat KM; QBI Coronavirus Research Group (QCRG), San Francisco, CA 94158, USA.
  • Krogan NJ; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.
  • García-Sastre A; Quantitative Biosciences Institute (QBI), University of California, San Francisco, CA 94158, USA.
Science ; 371(6532): 926-931, 2021 02 26.
Article in English | MEDLINE | ID: covidwho-1048642
Semantic information from SemMedBD (by NLM)
1. Proteins PART_OF 2019 novel coronavirus
Subject
Proteins
Predicate
PART_OF
Object
2019 novel coronavirus
2. aplidin compared_with remdesivir
Subject
aplidin
Predicate
compared_with
Object
remdesivir
3. aplidin higher_than remdesivir
Subject
aplidin
Predicate
higher_than
Object
remdesivir
4. plitidepsin INHIBITS EEF1A1 gene|EEF1A1
Subject
plitidepsin
Predicate
INHIBITS
Object
EEF1A1 gene|EEF1A1
5. plitidepsin TREATS Mouse Model
Subject
plitidepsin
Predicate
TREATS
Object
Mouse Model
6. Lung LOCATION_OF COVID-19
Subject
Lung
Predicate
LOCATION_OF
Object
COVID-19
7. COVID-19 DISRUPTS Virus Replication
Subject
COVID-19
Predicate
DISRUPTS
Object
Virus Replication
8. Proteins PART_OF 2019 novel coronavirus
Subject
Proteins
Predicate
PART_OF
Object
2019 novel coronavirus
9. aplidin compared_with remdesivir
Subject
aplidin
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compared_with
Object
remdesivir
10. aplidin higher_than remdesivir
Subject
aplidin
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higher_than
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remdesivir
11. plitidepsin INHIBITS EEF1A1 gene|EEF1A1
Subject
plitidepsin
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INHIBITS
Object
EEF1A1 gene|EEF1A1
12. plitidepsin TREATS Mouse Model
Subject
plitidepsin
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TREATS
Object
Mouse Model
13. Lung LOCATION_OF COVID-19
Subject
Lung
Predicate
LOCATION_OF
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COVID-19
14. COVID-19 DISRUPTS Virus Replication
Subject
COVID-19
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DISRUPTS
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Virus Replication
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins interact with the eukaryotic translation machinery, and inhibitors of translation have potent antiviral effects. We found that the drug plitidepsin (aplidin), which has limited clinical approval, possesses antiviral activity (90% inhibitory concentration = 0.88 nM) that is more potent than remdesivir against SARS-CoV-2 in vitro by a factor of 27.5, with limited toxicity in cell culture. Through the use of a drug-resistant mutant, we show that the antiviral activity of plitidepsin against SARS-CoV-2 is mediated through inhibition of the known target eEF1A (eukaryotic translation elongation factor 1A). We demonstrate the in vivo efficacy of plitidepsin treatment in two mouse models of SARS-CoV-2 infection with a reduction of viral replication in the lungs by two orders of magnitude using prophylactic treatment. Our results indicate that plitidepsin is a promising therapeutic candidate for COVID-19.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Peptide Elongation Factor 1 / Depsipeptides / SARS-CoV-2 / COVID-19 Type of study: Prognostic study Topics: Traditional medicine Limits: Animals / Female / Humans Language: English Journal: Science Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Peptide Elongation Factor 1 / Depsipeptides / SARS-CoV-2 / COVID-19 Type of study: Prognostic study Topics: Traditional medicine Limits: Animals / Female / Humans Language: English Journal: Science Year: 2021 Document Type: Article