ArticlePLoS neglected tropical diseases2011
Functional expression of parasite drug targets and their human orthologs in yeast.
Article in PLoS neglected tropical diseases, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 41 citations in OpenAlex.
- Chemometric modeling, inverse docking, and molecular simulations-driven design for multilayered prioritization of novel leishmanicidal agents based on a 2-aminobenzimidazole scaffold.Molecular diversity · 2026Article
- An experimental target-based platform in yeast for screening Plasmodium vivax deoxyhypusine synthase inhibitors.PLoS neglected tropical diseases · 2024Article
- Deep mutational scanning of Pneumocystis jirovecii dihydrofolate reductase reveals allosteric mechanism of resistance to an antifolate.PLoS genetics · 2024Article
- A Small Molecule Inhibitor of Pex3-Pex19 Interaction Disrupts Glycosome Biogenesis and Causes Lethality inFrontiers in cell and developmental biology · 2021Article
- Heterologous Expression of a Novel Drug Transporter from the Malaria Parasite Alters Resistance to Quinoline Antimalarials.Scientific reports · 2018Article
- Plasmodium dihydrofolate reductase is a second enzyme target for the antimalarial action of triclosan.Scientific reports · 2018Article
- Pyrimidine metabolism in schistosomes: A comparison with other parasites and the search for potential chemotherapeutic targets.Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology · 2017Review
- The Candidate Antimalarial Drug MMV665909 Causes Oxygen-Dependent mRNA Mistranslation and Synergizes with Quinoline-Derived Antimalarials.Antimicrobial agents and chemotherapy · 2017Article
- Yeast-Based High-Throughput Screens to Identify Novel Compounds Active against Brugia malayi.PLoS neglected tropical diseases · 2016Article
- Cheaper faster drug development validated by the repositioning of drugs against neglected tropical diseases.Journal of the Royal Society, Interface · 2015Article
- Identification and deconvolution of cross-resistance signals from antimalarial compounds using multidrug-resistant Plasmodium falciparum strains.Antimicrobial agents and chemotherapy · 2015Article
- Predicting complex phenotype-genotype interactions to enable yeast engineering: Saccharomyces cerevisiae as a model organism and a cell factory.Biotechnology journal · 2013Review
- Yeast-based automated high-throughput screens to identify anti-parasitic lead compounds.Open biology · 2013Article
- Identification and functional analysis of Trypanosoma cruzi genes that encode proteins of the glycosylphosphatidylinositol biosynthetic pathway.PLoS neglected tropical diseases · 2013Article
- Genome-wide assessment of the carriers involved in the cellular uptake of drugs: a model system in yeast.BMC biology · 2011Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundThe exacting nutritional requirements and complicated life cycles of parasites mean that they are not always amenable to high-throughput drug screening using automated procedures. Therefore, we have engineered the yeast Saccharomyces cerevisiae to act as a surrogate for expressing anti-parasitic targets from a range of biomedically important pathogens, to facilitate the rapid identification of new therapeutic agents. METHODOLOGY/PRINCIPAL
findingsUsing pyrimethamine/dihydrofolate reductase (DHFR) as a model parasite drug/drug target system, we explore the potential of engineered yeast strains (expressing DHFR enzymes from Plasmodium falciparum, P. vivax, Homo sapiens, Schistosoma mansoni, Leishmania major, Trypanosoma brucei and T. cruzi) to exhibit appropriate differential sensitivity to pyrimethamine. Here, we demonstrate that yeast strains (lacking the major drug efflux pump, Pdr5p) expressing yeast ((Sc)DFR1), human ((Hs)DHFR), Schistosoma ((Sm)DHFR), and Trypanosoma ((Tb)DHFR and (Tc)DHFR) DHFRs are insensitive to pyrimethamine treatment, whereas yeast strains producing Plasmodium ((Pf)DHFR and (Pv)DHFR) DHFRs are hypersensitive. Reassuringly, yeast strains expressing field-verified, drug-resistant mutants of P. falciparum DHFR ((Pf)dhfr(51I,59R,108N)) are completely insensitive to pyrimethamine, further validating our approach to drug screening. We further show the versatility of the approach by replacing yeast essential genes with other potential drug targets, namely phosphoglycerate kinases (PGKs) and N-myristoyl transferases (NMTs). CONCLUSIONS/SIGNIFICANCE: We have generated a number of yeast strains that can be successfully harnessed for the rapid and selective identification of urgently needed anti-parasitic agents.
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