Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2

Autor: Veronica V. Rezelj, Audrey Fischer, Francesca Moretti, Romel Rosales, Olivier Schwartz, Jiankun Lyu, Francois Pognan, Andrew C. Kruse, Kris M. White, Marco Vignuzzi, Heiko Schadt, Ziyang Zhang, Henry R. O’Donnell, Michael Schotsaert, Kevan M. Shokat, Tia A. Tummino, Adolfo García-Sastre, Nevan J. Krogan, Jean-Rene Galarneau, Raveen Rathnasinghe, Blandine Monel, Benoit Fischer, Briana L. McGovern, Assaf Alon, Matthew J. O’Meara, Thomas Vallet, Brian K. Shoichet, Sonia Jangra, Laszlo Urban
Přispěvatelé: University of California [San Francisco] (UC San Francisco), University of California (UC), Populations virales et Pathogenèse - Viral Populations and Pathogenesis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Novartis Institutes for BioMedical Research (NIBR), University of Michigan [Ann Arbor], University of Michigan System, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Harvard Medical School [Boston] (HMS), This work was supported by grants from the Defense Advanced Research Projects Agency (HR0011-19-2-0020 to B.K.S., N.J.K., A.G.-S., and K.M.S.), NIGMS R35GM122481 (to B.K.S.), National Institutes of Health (P50AI150476, U19AI135990, U19AI135972, R01AI143292, R01AI120694, P01AI063302, and R01AI122747 to N.J.K.), Excellence in Research Award (ERA) from the Laboratory for Genomics Research (LGR) (to N.J.K.), a collaboration between UCSF, UCB, and GSK (no. 133122P to N.J.K.), a Fast Grant for COVID-19 from the Emergent Ventures program at the Mercatus Center of George Mason University (to N.J.K.), funding from the Roddenberry Foundation (to N.J.K.), funding from F. Hoffmann–La Roche and Vir Biotechnology (to N.J.K.), gifts from QCRG philanthropic donors (to N.J.K.), funding from Institut Pasteur (to O.S. and M.V.), Urgence COVID-19 Fundraising Campaign of Institut Pasteur (to O.S. and M.V.), Labex IBEID (ANR-10-LABX-62-IBEID to O.S. and M.V.), ANR/FRM Flash Covid PROTEO-SARS-CoV-2 (to O.S.), IDISCOVR (to O.S.), National Institutes of Health (R01GM119185 to A.C.K.), partly supported by the Center for Research for Influenza Pathogenesis, a Center of Excellence for Influenza Research and Surveillance supported by the National Institute of Allergy and Infectious Diseases (contract no. HHSN272201400008C to A.G.-S.), a supplement to NIAID grant U19AI135972 and to DoD grant W81XWH-20-1-0270 (to A.G.-S.), a Fast Grant from the Mercatus Center (to A.G.-S.), the generous support of the JPB Foundation and the Open Philanthropy Project [research grant 2020-215611 (5384) to A.G.-S.], and anonymous donors (to A.G.-S.). Z.Z. is a Damon Runyon fellow supported by the Damon Runyon Cancer Research Foundation (DRG-2281-17)., We gratefully acknowledge the Région Ile-de-France (program DIM1Health) for the use of the Institut Pasteur imaging facility. We thank N. Aulner for assistance with image requisition and A. Danckaert for assistance with image analysis at Institut Pasteur, Paris. We thank R. Albrecht for support with the BSL3 facility and procedures at the Icahn School of Medicine at Mount Sinai, New York. We thank C. Hayden for the work with the transmission electron microscopy at Novartis. We thank T. R. O’Meara for reading the manuscript. We thank K. Obernier, M. Bouhaddou, and J. M. Fabius for contributions to the overall COVID-19 effort at QCRG., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020)
Rok vydání: 2021
Předmět:
Zdroj: Science (New York, N.Y.)
Science (New York, N.Y.), vol 373, iss 6554
Science
Science, 2021, 373 (6554), pp.541-547. ⟨10.1126/science.abi4708⟩
ISSN: 1095-9203
0036-8075
DOI: 10.1126/science.abi4708
Popis: International audience; Repurposing drugs as treatments for COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has drawn much attention. Beginning with sigma receptor ligands and expanding to other drugs from screening in the field, we became concerned that phospholipidosis was a shared mechanism underlying the antiviral activity of many repurposed drugs. For all of the 23 cationic amphiphilic drugs we tested, including hydroxychloroquine, azithromycin, amiodarone, and four others already in clinical trials, phospholipidosis was monotonically correlated with antiviral efficacy. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the physicochemical properties of drugs and does not reflect specific target-based activities—rather, it may be considered a toxic confound in early drug discovery. Early detection of phospholipidosis could eliminate these artifacts, enabling a focus on molecules with therapeutic potential.
Databáze: OpenAIRE
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