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

Tia A Tummino ,Briana L Mcgovern ,Henry R O'donnell ,Sonia Jangra ,Olivier Schwartz ,Romel Rosales ,Nevan J Krogan ,Thomas Vallet ,Jiankun Lyu ,Kevan M Shokat ,Jean-René Galarneau ,Audrey Fischer ,Heiko S Schadt ,Veronica V Rezelj ,Raveen Rathnasinghe ,Adolfo Garcı́a-Sastre ,Assaf Alon ,László Urbán ,Andrew C Kruse ,Michael Schotsaert ,Kris M White ,Marco Vignuzzi ,Ziyang Zhang ,Matthew J O’meara ,Benoit Fischer ,François Philippe ,Blandine Monel ,Francesca Moretti ,Brian K Shoichet

doi:10.1126/science.abi4708

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.

Highlights

If the cationic-amphiphilic nature of these molecules led to antiviral activity in vitro, rather than their target-based
As an effect that rarely occurs at concentrations lower than 100 nM, that does not appear to translate from in vitro to in vivo antiviral activity, and that can result in dose-limiting toxicity [19], phospholipidosis may be a confound to true antiviral drug discovery
We explore the prevalence of this confound in SARS-CoV-2 repurposing studies, how phospholipidosis correlates with inhibition of viral infection, and how to eliminate such hits rapidly so as to focus on drugs with genuine potential against COVID-19, and against new pandemics yet to arise

Summary

Introduction

If the cationic-amphiphilic nature of these molecules led to antiviral activity in vitro, rather than their target-based. We explore the prevalence of this confound in SARS-CoV-2 repurposing studies, how phospholipidosis correlates with inhibition of viral infection, and how to eliminate such hits rapidly so as to focus on drugs with genuine potential against COVID-19, and against new pandemics yet to arise.

Results

Conclusion