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

Tia A. Tummino; Veronica V. Rezelj; Benoit Fischer; Audrey Fischer; Matthew J. O’Meara; Blandine Monel; Thomas Vallet; Kris M. White; Ziyang Zhang; Assaf Alon; Heiko Schadt; Henry R. O’Donnell; Jiankun Lyu; Romel Rosales; Briana L. McGovern; Raveen Rathnasinghe; Sonia Jangra; Michael Schotsaert; Jean René Galarneau; Nevan J. Krogan; Laszlo Urban; Kevan M. Shokat; Andrew C. Kruse; Adolfo García-Sastre; Olivier Schwartz; Francesca Moretti; Marco Vignuzzi; Francois Pognan; Brian K. Shoichet

doi:10.1126/science.abi4708

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

Tia A. Tummino, Veronica V. Rezelj, Benoit Fischer, Audrey Fischer, Matthew J. O’Meara, Blandine Monel, Thomas Vallet, Kris M. White, Ziyang Zhang, Assaf Alon, Heiko Schadt, Henry R. O’Donnell, Jiankun Lyu, Romel Rosales, Briana L. McGovern, Raveen Rathnasinghe, Sonia Jangra, Michael Schotsaert, Jean René Galarneau, Nevan J. KroganLaszlo Urban, Kevan M. Shokat, Andrew C. Kruse, Adolfo García-Sastre, Olivier Schwartz, Francesca Moretti, Marco Vignuzzi, Francois Pognan, Brian K. Shoichet

Research output: Contribution to journal › Article › peer-review

134 Scopus citations

Abstract

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.

Original language	English
Article number	6554
Journal	Science
Volume	373
Issue number	6554
DOIs	https://doi.org/10.1126/science.abi4708
State	Published - 30 Jul 2021

Access to Document

10.1126/science.abi4708

Cite this

Tummino, T. A., Rezelj, V. V., Fischer, B., Fischer, A., O’Meara, M. J., Monel, B., Vallet, T., White, K. M., Zhang, Z., Alon, A., Schadt, H., O’Donnell, H. R., Lyu, J., Rosales, R., McGovern, B. L., Rathnasinghe, R., Jangra, S., Schotsaert, M., Galarneau, J. R., ... Shoichet, B. K. (2021). Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2. Science, 373(6554), Article 6554. https://doi.org/10.1126/science.abi4708

@article{fde2539aa17f42f193b39fa475fbc574,

title = "Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2",

abstract = "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.",

author = "Tummino, {Tia A.} and Rezelj, {Veronica V.} and Benoit Fischer and Audrey Fischer and O{\textquoteright}Meara, {Matthew J.} and Blandine Monel and Thomas Vallet and White, {Kris M.} and Ziyang Zhang and Assaf Alon and Heiko Schadt and O{\textquoteright}Donnell, {Henry R.} and Jiankun Lyu and Romel Rosales and McGovern, {Briana L.} and Raveen Rathnasinghe and Sonia Jangra and Michael Schotsaert and Galarneau, {Jean Ren{\'e}} and Krogan, {Nevan J.} and Laszlo Urban and Shokat, {Kevan M.} and Kruse, {Andrew C.} and Adolfo Garc{\'i}a-Sastre and Olivier Schwartz and Francesca Moretti and Marco Vignuzzi and Francois Pognan and Shoichet, {Brian K.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = jul,

day = "30",

doi = "10.1126/science.abi4708",

language = "English",

volume = "373",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6554",

}

Tummino, TA, Rezelj, VV, Fischer, B, Fischer, A, O’Meara, MJ, Monel, B, Vallet, T, White, KM, Zhang, Z, Alon, A, Schadt, H, O’Donnell, HR, Lyu, J, Rosales, R, McGovern, BL, Rathnasinghe, R, Jangra, S, Schotsaert, M, Galarneau, JR, Krogan, NJ, Urban, L, Shokat, KM, Kruse, AC, García-Sastre, A, Schwartz, O, Moretti, F, Vignuzzi, M, Pognan, F & Shoichet, BK 2021, 'Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2', Science, vol. 373, no. 6554, 6554. https://doi.org/10.1126/science.abi4708

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.

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 -

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

Abstract

Access to Document

Fingerprint

Cite this