Yeast-based automated high-throughput screens to identify anti-parasitic lead compounds

Elizabeth Bilsland, Andrew Charles Sparkes, Kevin Stewart Williams, Harry J. Moss, Michaela de Clare, Pınar Pir, Jem Rowland, Wayne Aubrey, Ronald Pateman, Michael Young, Mark Carrington, Ross Donald King, Stephen G. Oliver

Research output: Contribution to journalArticlepeer-review

30 Citations (SciVal)
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Abstract

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.
Original languageEnglish
Article number120158
Number of pages14
JournalOpen Biology
Volume3
Issue number2
DOIs
Publication statusPublished - 27 Feb 2013

Keywords

  • drug screening
  • parasites
  • YEAST
  • automation
  • tropical diseases
  • Automation
  • Yeast
  • Parasites
  • Drug screening
  • Tropical diseases
  • Yeasts/drug effects
  • Trypanosoma brucei brucei/drug effects
  • Antiparasitic Agents/chemistry
  • Humans
  • Drug Discovery
  • Small Molecule Libraries/chemistry
  • High-Throughput Screening Assays
  • Trypanosomiasis, African/drug therapy
  • Lead/chemistry

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