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

Tia A. Tummino (1) , Veronica V. Rezelj (2) , Benoit Fischer (3) , Audrey Fischer (3) , Matthew J. O’meara (4) , Blandine Monel (5) , Thomas Vallet (2) , Kris M. White (6) , Ziyang Zhang (1) , Assaf Alon (7) , Heiko Schadt (3) , Henry R. O’donnell (1) , Jiankun Lyu (1) , Romel Rosales (6) , Briana L. Mcgovern (6) , Raveen Rathnasinghe (6) , Sonia Jangra (6) , Michael Schotsaert (6) , Jean-René Galarneau (3) , Nevan J. Krogan (1) , Laszlo Urban (3) , Kevan M. Shokat (1) , Andrew C. Kruse (7) , Adolfo García-Sastre (6) , Olivier Schwartz (5) , Francesca Moretti (3) , Marco Vignuzzi (2) , Francois Pognan (3) , Brian K. Shoichet (1)

1 UC San Francisco - University of California [San Francisco]
2 Populations virales et Pathogenèse - Viral Populations and Pathogenesis
3 NIBR - Novartis Institutes for BioMedical Research
4 University of Michigan [Ann Arbor]
5 CNRS-UMR3569 - Virus et Immunité - Virus and immunity
6 MSSM - Icahn School of Medicine at Mount Sinai [New York]
7 HMS - Harvard Medical School [Boston]

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.

Domaines: Virologie

Tia A. Tummino, Veronica V. Rezelj, Benoit Fischer, Audrey Fischer, Matthew J. O’meara, et al.. Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2. Science, 2021, 373 (6554), pp.541-547. ⟨10.1126/science.abi4708⟩. ⟨pasteur-03696873⟩