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

Screening for drugs that don't work In the battle against COVID-19, drugs discovered in repurposing screens are of particular interest because these could be rapidly implemented as treatments. However, Tummino et al. deliver a cautionary tale, finding that many leads from such screens have an antiviral effect in cells through phospholipidosis, a phospholipid storage disorder that can be induced by cationic amphiphilic drugs (see the Perspective by Edwards and Hartung). There is a strong correlation between drug-induced phospholipidosis and inhibition of severe acute respiratory syndrome coronavirus 2 replication in cells. Unfortunately, drugs that have an antiviral effect in cells through phospholipidosis are unlikely to be effective in vivo. Screening out such drugs may allow a focus on drugs with better clinical potential. Science, abi4708, this issue p. 541; see also abj9488, p. 488 Phospholipidosis is a shared mechanism underlying the in vitro antiviral activity of many repurposed drugs against SARS-CoV-2. 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.