Nuisance compounds in cellular assays

Dahlin, Jayme L.; Auld, Douglas S.; Rothenaigner, Ina; Haney, Steve; Sexton, Jonathan Z.; Nissink, J. Willem M.; Walsh, Jarrod; Lee, Jonathan A.; Strelow, John; Willard, Francis S.; Ferrins, Lori; Baell, Jonathan B.; Walters, Michael A.; Hua, Bruce K.; Hadian, Kamyar; Wagner, Bridget K.

doi:10.1016/j.chembiol.2021.01.021

Cited by 43 publications

(39 citation statements)

References 139 publications

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“…We further noticed that this cationic-amphiphilic character was also shared among many of the hits emerging from other phenotypic screens ( Fig. 1 , S10 ), suggesting it was this physico-chemical property that might explain antiviral activity, instead of a specific on-target activity( 5 ).…”

Section: Main Textmentioning

confidence: 82%

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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Section: Main Textmentioning

confidence: 82%

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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“…Our analysis also established that 132 compounds were flagged with one or more structural alerts from either a) PAINS filters, 47,48 b) aggregators, 49 c) cellular assay nuisance compounds 50 or d) historical compounds. Of the 60 stereoisomers, 54 originate from the Probe Miner set.…”

Section: Dataset Compilationmentioning

confidence: 97%

Will the chemical probes please stand up?

2021

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“…To this date, potential assay interference compounds frequently remain unrecognized in publications and there is still room for improvement in their detection and further evaluation. Importantly, the study of interference compounds in different types of assays continues to be an active area of research [18] and, while already far advanced through the concepts discussed herein, still provides many opportunities for future scientifc work.…”

Section: Expert Opinionmentioning

confidence: 99%

Evolution of assay interference concepts in drug discovery

Bajorath

2021

Expert Opinion on Drug Discovery

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Nuisance compounds in cellular assays

Cited by 43 publications

References 139 publications

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

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

Will the chemical probes please stand up?

Evolution of assay interference concepts in drug discovery

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