Unraveling the antiviral activity of plitidepsin against SARS-CoV-2 by subcellular and morphological analysis
Sachse, Martin (Centro Nacional de Biotecnología)
Tenorio, Raquel (Centro Nacional de Biotecnología)
Fernández de Castro, Isabel (Centro Nacional de Biotecnología)
Muñoz-Basagoiti, Jordana (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Perez-Zsolt, Daniel (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Raïch-Regué, Dàlia (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Rodon, Jordi (Universitat Autònoma de Barcelona. Departament de Sanitat i d'Anatomia Animals)
Losada, Alejandro (PharmaMar S.A)
Avilés, Pablo (PharmaMar S.A)
Cuevas, Carmen (PharmaMar S.A)
Paredes, Roger (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Segalés Coma, Joaquim (Universitat Autònoma de Barcelona. Departament de Sanitat i d'Anatomia Animals)
Clotet Sala, Bonaventura (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Vergara-Alert, Júlia (Universitat Autònoma de Barcelona. Departament de Sanitat i d'Anatomia Animals)
Izquierdo Useros, Nuria (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Risco, Cristina (Centro Nacional de Biotecnología)
Date: |
2022 |
Abstract: |
The pandemic caused by the new coronavirus SARS-CoV-2 has made evident the need for broad-spectrum, efficient antiviral treatments to combat emerging and re-emerging viruses. Plitidepsin is an antitumor agent of marine origin that has also shown a potent pre-clinical efficacy against SARS-CoV-2. Plitidepsin targets the host protein eEF1A (eukaryotic translation elongation factor 1 alpha) and affects viral infection at an early, post-entry step. Because electron microscopy is a valuable tool to study virus-cell interactions and the mechanism of action of antiviral drugs, in this work we have used transmission electron microscopy (TEM) to evaluate the effects of plitidepsin in SARS-CoV-2 infection in cultured Vero E6 cells 24 and 48h post-infection. In the absence of plitidepsin, TEM morphological analysis showed double-membrane vesicles (DMVs), organelles that support coronavirus genome replication, single-membrane vesicles with viral particles, large vacuoles with groups of viruses and numerous extracellular virions attached to the plasma membrane. When treated with plitidepsin, no viral structures were found in SARS-CoV-2-infected Vero E6 cells. Immunogold detection of SARS-CoV-2 nucleocapsid (N) protein and double-stranded RNA (dsRNA) provided clear signals in cells infected in the absence of plitidepsin, but complete absence in cells infected and treated with plitidepsin. The present study shows that plitidepsin blocks the biogenesis of viral replication organelles and the morphogenesis of virus progeny. Electron microscopy morphological analysis coupled to immunogold labeling of SARS-CoV-2 products offers a unique approach to understand how antivirals such as plitidepsin work. |
Grants: |
Agencia Estatal de Investigación PID2020-117145RB-I00 Agencia Estatal de Investigación RTI2018-094445-B-I00
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Rights: |
Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades. |
Language: |
Anglès |
Document: |
Article ; recerca ; Versió publicada |
Subject: |
Antiviral ;
Covid-19 ;
Electron microscopy ;
Plitidepsin ;
SARS-CoV-2 |
Published in: |
Antiviral Research, Vol. 200 (february 2022) , p. 105270, ISSN 1872-9096 |
DOI: 10.1016/j.antiviral.2022.105270
PMID: 35231500
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Record created 2022-03-22, last modified 2024-04-25