On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2

• Published in: Cell death & disease Vol. 11; no. 8; p. 656
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.08.2020; Springer Nature B.V; Nature Publishing Group
• Subjects: 38/77; 631/154/1435/2418; 692/699/255/2514; Animals; Antibodies; Antiviral agents; Antiviral Agents - pharmacology; Betacoronavirus - physiology; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Death - drug effects; Chlorocebus aethiops; Chloroquine; Chlorpromazine; Coronaviridae; Coronavirus Infections - metabolism; Coronavirus Infections - virology; Coronaviruses; COVID-19; Drug Evaluation, Preclinical - methods; Emetine; Endosomes; Enzyme inhibitors; Haloperidol; Hydroxychloroquine; Hydroxychloroquine - pharmacology; Imatinib; Imatinib Mesylate - pharmacology; Immunology; Life Sciences; Lipophilic; Lysosomes; Lysosomes - drug effects; Medicin och hälsovetenskap; Microbiology and Parasitology; Organelles; Pandemics; Phagosomes; Pharmaceutical sciences; Pharmacology; Pneumonia, Viral - metabolism; Pneumonia, Viral - virology; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Quantitative Methods; Replication; RNA, Viral - drug effects; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Vero Cells; Viral Load - drug effects; Virology; Virus Replication - drug effects
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-02842-x

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.