Yeast-based automated high-throughput screens to identify anti-parasitic lead compounds
We have developed a robust, fully automated anti-parasitic drug-screening method that selects compounds specifically targeting parasite enzymes and not their host counterparts, thus allowing the early elimination of compounds with potential side effects. Our yeast system permits multiple parasite ta...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
The Royal Society
2013-01-01
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| Series: | Open Biology |
| Subjects: | |
| Online Access: | https://royalsocietypublishing.org/doi/pdf/10.1098/rsob.120158 |
| _version_ | 1819009524466450432 |
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| author | Elizabeth Bilsland Andrew Sparkes Kevin Williams Harry J. Moss Michaela de Clare Pınar Pir Jem Rowland Wayne Aubrey Ron Pateman Mike Young Mark Carrington Ross D. King Stephen G. Oliver |
| author_facet | Elizabeth Bilsland Andrew Sparkes Kevin Williams Harry J. Moss Michaela de Clare Pınar Pir Jem Rowland Wayne Aubrey Ron Pateman Mike Young Mark Carrington Ross D. King Stephen G. Oliver |
| author_sort | Elizabeth Bilsland |
| collection | DOAJ |
| description | We have developed a robust, fully automated anti-parasitic drug-screening method that selects compounds specifically targeting parasite enzymes and not their host counterparts, thus allowing the early elimination of compounds with potential side effects. Our yeast system permits multiple parasite targets to be assayed in parallel owing to the strains’ expression of different fluorescent proteins. A strain expressing the human target is included in the multiplexed screen to exclude compounds that do not discriminate between host and parasite enzymes. This form of assay has the advantages of using known targets and not requiring the in vitro culture of parasites. We performed automated screens for inhibitors of parasite dihydrofolate reductases, N-myristoyltransferases and phosphoglycerate kinases, finding specific inhibitors of parasite targets. We found that our ‘hits’ have significant structural similarities to compounds with in vitro anti-parasitic activity, validating our screens and suggesting targets for hits identified in parasite-based assays. Finally, we demonstrate a 60 per cent success rate for our hit compounds in killing or severely inhibiting the growth of Trypanosoma brucei, the causative agent of African sleeping sickness. |
| first_indexed | 2024-12-21T00:57:44Z |
| format | Article |
| id | doaj.art-068f2d8a3cbc4d3c85128c2a049a3abc |
| institution | Directory Open Access Journal |
| issn | 2046-2441 |
| language | English |
| last_indexed | 2024-12-21T00:57:44Z |
| publishDate | 2013-01-01 |
| publisher | The Royal Society |
| record_format | Article |
| series | Open Biology |
| spelling | doaj.art-068f2d8a3cbc4d3c85128c2a049a3abc2022-12-21T19:21:14ZengThe Royal SocietyOpen Biology2046-24412013-01-013210.1098/rsob.120158120158Yeast-based automated high-throughput screens to identify anti-parasitic lead compoundsElizabeth BilslandAndrew SparkesKevin WilliamsHarry J. MossMichaela de ClarePınar PirJem RowlandWayne AubreyRon PatemanMike YoungMark CarringtonRoss D. KingStephen G. OliverWe have developed a robust, fully automated anti-parasitic drug-screening method that selects compounds specifically targeting parasite enzymes and not their host counterparts, thus allowing the early elimination of compounds with potential side effects. Our yeast system permits multiple parasite targets to be assayed in parallel owing to the strains’ expression of different fluorescent proteins. A strain expressing the human target is included in the multiplexed screen to exclude compounds that do not discriminate between host and parasite enzymes. This form of assay has the advantages of using known targets and not requiring the in vitro culture of parasites. We performed automated screens for inhibitors of parasite dihydrofolate reductases, N-myristoyltransferases and phosphoglycerate kinases, finding specific inhibitors of parasite targets. We found that our ‘hits’ have significant structural similarities to compounds with in vitro anti-parasitic activity, validating our screens and suggesting targets for hits identified in parasite-based assays. Finally, we demonstrate a 60 per cent success rate for our hit compounds in killing or severely inhibiting the growth of Trypanosoma brucei, the causative agent of African sleeping sickness.https://royalsocietypublishing.org/doi/pdf/10.1098/rsob.120158drug screeningparasitesyeastautomationtropical diseases |
| spellingShingle | Elizabeth Bilsland Andrew Sparkes Kevin Williams Harry J. Moss Michaela de Clare Pınar Pir Jem Rowland Wayne Aubrey Ron Pateman Mike Young Mark Carrington Ross D. King Stephen G. Oliver Yeast-based automated high-throughput screens to identify anti-parasitic lead compounds Open Biology drug screening parasites yeast automation tropical diseases |
| title | Yeast-based automated high-throughput screens to identify anti-parasitic lead compounds |
| title_full | Yeast-based automated high-throughput screens to identify anti-parasitic lead compounds |
| title_fullStr | Yeast-based automated high-throughput screens to identify anti-parasitic lead compounds |
| title_full_unstemmed | Yeast-based automated high-throughput screens to identify anti-parasitic lead compounds |
| title_short | Yeast-based automated high-throughput screens to identify anti-parasitic lead compounds |
| title_sort | yeast based automated high throughput screens to identify anti parasitic lead compounds |
| topic | drug screening parasites yeast automation tropical diseases |
| url | https://royalsocietypublishing.org/doi/pdf/10.1098/rsob.120158 |
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