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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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Detalles Bibliográficos
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
Descripción
Sumario: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.