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

Allan Sauvat (1, 2) , Fabiola Ciccosanti (3, 4) , Francesca Colavita (3, 4) , Martina Di Rienzo (3, 4) , Concetta Castilletti (3, 4) , Maria Rosaria Capobianchi (3, 4) , Oliver Kepp (1, 2) , Laurence Zitvogel (2, 5, 6, 7, 8) , Gian Maria Fimia (4, 3) , Mauro Piacentini (4, 9) , Guido Kroemer (1, 2, 10, 11, 12)

1 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
2 IGR - Institut Gustave Roussy
3 IRCCS - Istituti di Ricovero e Cura a Carattere Scientifico
4 National Institute for Infectious Diseases "Lazzaro Spallanzani"
5 INTIM - Immunologie intégrative des tumeurs et immunothérapie des cancers
6 CIC 1428 , CBT 507 - Centre d'Investigation Clinique en Biotherapie des cancers
7 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
8 ITIC - Immunologie anti-tumorale et immunothérapie des cancers
9 Università degli Studi di Roma Tor Vergata [Roma] = University of Rome Tor Vergata
10 HEGP - Hôpital Européen Georges Pompidou [APHP]
11 Karolinska Institutet [Stockholm]
12 Karolinska University Hospital [Stockholm]

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.

Domaines: Pharmacologie; Bio-Informatique, Biologie Systémique [q-bio.QM]; Virologie

Allan Sauvat, Fabiola Ciccosanti, Francesca Colavita, Martina Di Rienzo, Concetta Castilletti, et al.. On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2. Cell Death and Disease, 2020, 11 (8), pp.656. ⟨10.1038/s41419-020-02842-x⟩. ⟨hal-02944721⟩