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On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2.
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.
  • Sauvat A; Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France.
  • Ciccosanti F; Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France.
  • Colavita F; Department of Epidemiology, Preclinical Research, and Advanced Diagnostics, National Institute for Infectious Diseases 'L. Spallanzani' IRCCS, Rome, Italy.
  • Di Rienzo M; Department of Epidemiology, Preclinical Research, and Advanced Diagnostics, National Institute for Infectious Diseases 'L. Spallanzani' IRCCS, Rome, Italy.
  • Castilletti C; Department of Epidemiology, Preclinical Research, and Advanced Diagnostics, National Institute for Infectious Diseases 'L. Spallanzani' IRCCS, Rome, Italy.
  • Capobianchi MR; Department of Epidemiology, Preclinical Research, and Advanced Diagnostics, National Institute for Infectious Diseases 'L. Spallanzani' IRCCS, Rome, Italy.
  • Kepp O; Department of Epidemiology, Preclinical Research, and Advanced Diagnostics, National Institute for Infectious Diseases 'L. Spallanzani' IRCCS, Rome, Italy.
  • Zitvogel L; Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM UMR1138, Centre de Recherche des Cordeliers, Paris, France.
  • Fimia GM; Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France.
  • Piacentini M; Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.
  • Kroemer G; INSERM U1015, Villejuif, France.
Cell Death Dis ; 11(8): 656, 2020 08 19.
Article in English | MEDLINE | ID: covidwho-725491
ABSTRACT
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pneumonia, Viral / Virus Replication / Coronavirus Infections / Drug Evaluation, Preclinical / Betacoronavirus Type of study: Experimental Studies / Prognostic study Topics: Traditional medicine Limits: Animals Language: English Journal: Cell Death Dis Year: 2020 Document Type: Article Affiliation country: S41419-020-02842-x

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pneumonia, Viral / Virus Replication / Coronavirus Infections / Drug Evaluation, Preclinical / Betacoronavirus Type of study: Experimental Studies / Prognostic study Topics: Traditional medicine Limits: Animals Language: English Journal: Cell Death Dis Year: 2020 Document Type: Article Affiliation country: S41419-020-02842-x