Drug screening in <i>Drosophila</i>; why, when, and when not?

Su, Tin Tin

doi:10.1002/wdev.346

Cited by 48 publications

(29 citation statements)

References 85 publications

(123 reference statements)

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“…This provides limited possibility to investigate the impact of genetic background on drug efficiency and genotype specific unwanted side effects. Therefore, small model organism like Drosophila melanogaster, have been suggested as promising model system for testing pharmacological interventions [20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Genotype and Trait Specific Responses to Rapamycin Intake in Drosophila melanogaster

Rohde

Bøcker

Jensen

et al. 2021

Insects

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Rapamycin is a powerful inhibitor of the TOR (Target of Rapamycin) pathway, which is an evolutionarily conserved protein kinase, that plays a central role in plants and animals. Rapamycin is used globally as an immunosuppressant and as an anti-aging medicine. Despite widespread use, treatment efficiency varies considerably across patients, and little is known about potential side effects. Here we seek to investigate the effects of rapamycin by using Drosophila melanogaster as model system. Six isogenic D. melanogaster lines were assessed for their fecundity, male longevity and male heat stress tolerance with or without rapamycin treatment. The results showed increased longevity and heat stress tolerance for male flies treated with rapamycin. Conversely, the fecundity of rapamycin-exposed individuals was lower than for flies from the non-treated group, suggesting unwanted side effects of the drug in D. melanogaster. We found strong evidence for genotype-by-treatment interactions suggesting that a ‘one size fits all’ approach when it comes to treatment with rapamycin is not recommendable. The beneficial responses to rapamycin exposure for stress tolerance and longevity are in agreement with previous findings, however, the unexpected effects on reproduction are worrying and need further investigation and question common believes that rapamycin constitutes a harmless drug.

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Section: Introductionmentioning

confidence: 99%

Genotype and Trait Specific Responses to Rapamycin Intake in Drosophila melanogaster

Rohde

Bøcker

Jensen

et al. 2021

Insects

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“…It is made The copyright holder for this preprint this version posted December 20, 2020. ; https://doi.org/10.1101/2020.12.20.423533 doi: bioRxiv preprint 3 underlie viral infections (Hao et al, 2008;Hughes et al, 2012;Yang et al, 2018), and that contribute to viral pathogenicity (Adamson et al, 2011;Chan et al, 2009;Harsh et al, 2020). In addition, the short lifespan with easy-to-score visible phenotypes has made the fruit fly a productive in vivo drug screening platform (Chang et al, 2008;Dar et al, 2012;Su, 2019;Willoughby et al, 2013). Here, we report the development and characterization of an in vivo Drosophila model that assays SARS-CoV-2 proteins for tissue-specific pathogenicity and that can successfully identify drug candidates that mitigate pathogenic SARS-CoV-2 proteins.…”

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confidence: 99%

Infection and chronic disease activate a brain-muscle signaling axis that regulates muscle performance

Yang¹,

Tian

An³

2020

Preprint

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SummaryThe Coronavirus Disease 2019 (COVID-19) pandemic has caused millions of deaths and will continue to exact incalculable tolls worldwide. While great strides have been made toward understanding and combating the mechanisms of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection, relatively little is known about the individual SARS-CoV-2 proteins that contribute to pathogenicity during infection and that cause neurological sequela after viral clearance. We used Drosophila to develop an in vivo model that characterizes mechanisms of SARS-CoV-2 pathogenicity, and found ORF3a adversely affects longevity and motor function by inducing apoptosis and inflammation in the nervous system. Chloroquine alleviated ORF3a induced phenotypes in the CNS, arguing our Drosophila model is amenable to high throughput drug screening. Our work provides novel insights into the pathogenic nature of SARS-CoV-2 in the nervous system that can be used to develop new treatment strategies for post-viral syndrome.HighlightsSARS-CoV-2 ORF3a is pathogenic in the nervous system.ORF3a induces cell death, inflammation, and lysosome dysfunction.Chloroquine protects against ORF3a induced CNS distress and lysosome dysfunction.

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“…The fly D. melanogaster is a proven model organism for evaluating the effects of a particular drug on a human mutation ( Su, 2019 ). Studies have shown that drugs that act on a diversity of cellular targets like the cytoskeleton, kinases, phosphatases, ion channels, cell surface receptors, chaperones, and proteases often have the same target, or act through the same mechanism, in Drosophila as in humans ( Fernandez-Hernandez et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts

Liu

Weaver

Sen

et al. 2021

Front. Cell Dev. Biol.

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Peroxisome biogenesis disorders (PBDs) are a group of metabolic developmental diseases caused by mutations in one or more genes encoding peroxisomal proteins. Zellweger syndrome spectrum (PBD-ZSS) results from metabolic dysfunction caused by damaged or non-functional peroxisomes and manifests as a multi-organ syndrome with significant morbidity and mortality for which there is no current drug therapy. Mild PBD-ZSS patients can exhibit a more progressive disease course and could benefit from the identification of drugs to improve the quality of life and extend the lifespan of affected individuals. Our study used a high-throughput screen of FDA-approved compounds to identify compounds that improve peroxisome function and biogenesis in human fibroblast cells carrying the mild PBD-ZSS variant, PEX1G843D. Our screen identified the nitrogen oxide donor, S-nitrosoglutathione (GSNO), as a potential therapeutic for this mild form of PBD-ZSS. Further biochemical characterization showed that GSNO enhances both peroxisome number and function in PEX1G843D mutant fibroblasts and leads to increased survival and longer lifespan in an in vivo humanized Drosophila model carrying the PEX1G843D mutation. GSNO is therefore a strong candidate to be translated to clinical trials as a potential therapeutic for mild PBD-ZSS.

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Drug screening in Drosophila; why, when, and when not?

Cited by 48 publications

References 85 publications

Genotype and Trait Specific Responses to Rapamycin Intake in Drosophila melanogaster

Genotype and Trait Specific Responses to Rapamycin Intake in Drosophila melanogaster

Infection and chronic disease activate a brain-muscle signaling axis that regulates muscle performance

The Nitric Oxide Donor, S-Nitrosoglutathione, Rescues Peroxisome Number and Activity Defects in PEX1G843D Mild Zellweger Syndrome Fibroblasts

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