Journal
SCIENCE
Volume 373, Issue 6554, Pages 541-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abi4708
Keywords
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Funding
- Defense Advanced Research Projects Agency [HR0011-19-2-0020]
- NIGMS [R35GM122481]
- National Institutes of Health [P50AI150476, U19AI135990, U19AI135972, R01AI143292, R01AI120694, P01AI063302, R01AI122747, R01GM119185]
- Excellence in Research Award (ERA) from the Laboratory for Genomics Research (LGR)
- UCSF [133122P]
- UCB [133122P]
- GSK [133122P]
- Fast Grant for COVID-19 from the Emergent Ventures program at the Mercatus Center of George Mason University
- Roddenberry Foundation
- F. Hoffmann-La Roche
- Vir Biotechnology
- Institut Pasteur
- Urgence COVID-19 Fundraising Campaign of Institut Pasteur
- Labex IBEID [ANR-10-LABX-62-IBEID]
- ANR/FRM Flash Covid [PROTEO-SARS-CoV-2]
- IDISCOVR
- Center for Research for Influenza Pathogenesis, a Center of Excellence for Influenza Research and Surveillance - National Institute of Allergy and Infectious Diseases [HHSN272201400008C]
- NIAID [U19AI135972]
- DoD [W81XWH-20-1-0270]
- Mercatus Center
- JPB Foundation
- Open Philanthropy Project [2020-215611 (5384)]
- Damon Runyon Cancer Research Foundation [DRG-2281-17]
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Phospholipidosis may be a shared mechanism underlying the antiviral activity of many repurposed drugs, and early detection and elimination of these effects can enable a focus on molecules with therapeutic potential.
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 targetbased 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.
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