On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2
Fecha
2020-08-19Autor
Sauvat, Allan
Ciccosanti, Fabiola
Colavita, Francesca
Di Rienzo, Martina
Castilletti, Concetta
Capobianchi, Maria Rosaria
Kepp, Oliver
Zitvogel, Laurence
Fimia, Gian Maria
Piacentini, Mauro
Kroemer, Guido
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Resumen en idioma extranjero
The current epidemic of coronavirus disease-19 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) calls for the development of inhibitors of viral replication. Here, we performed a bioinformatic analysis of published and purported SARS-CoV-2 antivirals including imatinib mesylate that we found to suppress SARS-CoV-2 replication on Vero E6 cells and that, according to the published literature on other coronaviruses is likely to act on-target, as a tyrosine kinase inhibitor. We identified a cluster of SARS-CoV-2 antivirals with characteristics of lysosomotropic agents, meaning that they are lipophilic weak bases capable of penetrating into cells. These agents include cepharentine, chloroquine, chlorpromazine, clemastine, cloperastine, emetine, hydroxychloroquine, haloperidol, ML240, PB28, ponatinib, siramesine, and zotatifin (eFT226) all of which are likely to inhibit SARS-CoV-2 replication by non-specific (off-target) effects, meaning that they probably do not act on their ‘official’ pharmacological targets, but rather interfere with viral replication through non-specific effects on acidophilic organelles including autophagosomes, endosomes, and lysosomes. Imatinib mesylate did not fall into this cluster. In conclusion, we propose a tentative classification of SARS-CoV-2 antivirals into specific (on-target) versus non-specific (off-target) agents based on their physicochemical characteristics.
Palabras clave
medicamentos que inhiben la replicación del SARS-CoV-2; epidemic of coronavirus disease; inhibitors of viralEnlace al recurso
https://www.nature.com/articles/s41419-020-02842-xColecciones
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