TY - JOUR
T1 - Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2
AU - Tummino, Tia A.
AU - Rezelj, Veronica V.
AU - Fischer, Benoit
AU - Fischer, Audrey
AU - O’Meara, Matthew J.
AU - Monel, Blandine
AU - Vallet, Thomas
AU - White, Kris M.
AU - Zhang, Ziyang
AU - Alon, Assaf
AU - Schadt, Heiko
AU - O’Donnell, Henry R.
AU - Lyu, Jiankun
AU - Rosales, Romel
AU - McGovern, Briana L.
AU - Rathnasinghe, Raveen
AU - Jangra, Sonia
AU - Schotsaert, Michael
AU - Galarneau, Jean René
AU - Krogan, Nevan J.
AU - Urban, Laszlo
AU - Shokat, Kevan M.
AU - Kruse, Andrew C.
AU - García-Sastre, Adolfo
AU - Schwartz, Olivier
AU - Moretti, Francesca
AU - Vignuzzi, Marco
AU - Pognan, Francois
AU - Shoichet, Brian K.
N1 - Funding Information:
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).
Publisher Copyright:
© 2021 The Authors
PY - 2021/7/30
Y1 - 2021/7/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85109550158&partnerID=8YFLogxK
U2 - 10.1126/science.abi4708
DO - 10.1126/science.abi4708
M3 - Article
C2 - 34326236
AN - SCOPUS:85109550158
SN - 0036-8075
VL - 373
JO - Science
JF - Science
IS - 6554
M1 - 6554
ER -