| Literature DB >> 33495306 |
Kris M White1,2, Romel Rosales3,2, Soner Yildiz3,2, Thomas Kehrer3,2, Lisa Miorin3,2, Elena Moreno3,2, Sonia Jangra3,2, Melissa B Uccellini3,2, Raveen Rathnasinghe3,2, Lynda Coughlan4, Carles Martinez-Romero3,2, Jyoti Batra5,6,7,8, Ajda Rojc5,6,7,8, Mehdi Bouhaddou5,6,7,8, Jacqueline M Fabius5,7, Kirsten Obernier5,6,7,8, Marion Dejosez9, María José Guillén10, Alejandro Losada10, Pablo Avilés10, Michael Schotsaert3,2, Thomas Zwaka9, Marco Vignuzzi11, Kevan M Shokat5,7,8,12, Nevan J Krogan1,5,6,7,8, Adolfo García-Sastre1,2,13,14.
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.Entities:
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Year: 2021 PMID： 33495306 PMCID： PMC7963220 DOI： 10.1126/science.abf4058
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728