SnapShot: Lysosomal Functions

Holland, Lya Katrine Kauffeldt; Nielsen, Inger Ødum; Maeda, Kenji; Jäättelä, Marja

doi:10.1016/j.cell.2020.03.043

Cited by 43 publications

(25 citation statements)

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“…Disruption of lipid homeostasis by the induction of phospholipidosis may disrupt these vesicles, reducing viral replication. The disruption of lysosomal ( 44 ) and endosomal ( 45 ) compartments and CAD-induced shifts in compartmental pH ( 46 ) may further affect viral entry and propagation ( 47 ). Accordingly, targeting the endosomal-lysosomal pathway has been suggested as a viable strategy against SARS-CoV-2 infection ( 48 ), but developing potent and targeted inhibitors remains challenging.…”

Section: Discussionmentioning

confidence: 99%

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

Tummino

Rezelj

Fischer

et al. 2021

Science

176

186

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Repurposing drugs as treatments for COVID-19 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 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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Tummino

Rezelj

Fischer

et al. 2021

Science

176

186

View full text Add to dashboard Cite

show abstract

“…Disruption of lipid homeostasis by the induction of phospholipidosis may lead to the formation of lipid structures that compete with or disrupt the formation of viral double membrane vesicles, reducing viral replication. Alternatively, the disruption of lysosomal( 50 ) and endosomal( 51 ) compartments by aggregating phospholipids and CAD-induced transient shifts in compartmental pH( 52 ) may further affect viral entry and propagation( 53 ). For example, it is possible that alterations to these compartments disrupt cathepsins that have been shown to prime the SARS-CoV-2 spike protein facilitating viral entry( 54 ).…”

Section: Discussionmentioning

confidence: 99%

Phospholipidosis is a shared mechanism underlying thein vitroantiviral activity of many repurposed drugs against SARS-CoV-2

Tummino

Fischer

et al. 2021

Preprint

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Repurposing drugs as treatments for COVID-19 has drawn much attention. A common strategy has been to screen for established drugs, typically developed for other indications, that are antiviral in cells or organisms. Intriguingly, most of the drugs that have emerged from these campaigns, though diverse in structure, share a common physical property: cationic amphiphilicity. Provoked by the similarity of these repurposed drugs to those inducing phospholipidosis, a well-known drug side effect, we investigated phospholipidosis as a mechanism for antiviral activity. We tested 23 cationic amphiphilic drugs-including those from phenotypic screens and others that we ourselves had found-for induction of phospholipidosis in cell culture. We found that most of the repurposed drugs, which included hydroxychloroquine, azithromycin, amiodarone, and four others that have already progressed to clinical trials, induced phospholipidosis in the same concentration range as their antiviral activity; indeed, there was a strong monotonic correlation between antiviral efficacy and the magnitude of the phospholipidosis. Conversely, drugs active against the same targets that did not induce phospholipidosis were not antiviral. Phospholipidosis depends on the gross physical properties of drugs, and does not reflect specific target-based activities, rather it may be considered a confound in early drug discovery. Understanding its role in infection, and detecting its effects rapidly, will allow the community to better distinguish between drugs and lead compounds that more directly impact COVID-19 from the large proportion of molecules that manifest this confounding effect, saving much time, effort and cost.

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“…43 Meanwhile, this 'stomach' of the cell controls the metabolism and signal hub of intracellular activities. 44 Therefore, the reformed, activated, or damaged lysosomes are a target to regulate degradation during autophagy. 45 Protective autophagy is precisely controlled to degrade the protein and reutilize damaged organelles.…”

Section: Organelle Membranementioning

confidence: 99%