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Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A

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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963220/
https://www.ncbi.nlm.nih.gov/pubmed/33495306
http://dx.doi.org/10.1126/science.abf4058
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author 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
author_facet 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
author_sort White, Kris M.
collection PubMed
description 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.
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spelling pubmed-79632202021-03-24 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 Science Research Articles 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. American Association for the Advancement of Science 2021-02-26 2021-01-25 /pmc/articles/PMC7963220/ /pubmed/33495306 http://dx.doi.org/10.1126/science.abf4058 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
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
Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A
title Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A
title_full Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A
title_fullStr Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A
title_full_unstemmed Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A
title_short Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A
title_sort plitidepsin has potent preclinical efficacy against sars-cov-2 by targeting the host protein eef1a
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963220/
https://www.ncbi.nlm.nih.gov/pubmed/33495306
http://dx.doi.org/10.1126/science.abf4058
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