Yeast: bridging the gap between phenotypic and biochemical assays for high-throughput screening

Denny, Paul W.

doi:10.1080/17460441.2018.1534826

Cited by 19 publications

(18 citation statements)

References 54 publications

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“…16,[84][85][86] Subsequently, to aid rational development towards the clinic, an understanding of the mode of action is vital. [87][88][89][90] Mass spectrometry-based metabolomics has been applied to investigate this for both clinical drugs and experimental natural compounds, although the results of these studies can be difficult to interpret. 28,91 Notably all but one, the natural cyclic peptide amphotericin B, of the current clinical anti-leishmanials lacks a well-defined mechanism of action.…”

Section: Rsc Medicinal Chemistrymentioning

confidence: 99%

An investigation of the antileishmanial properties of semi-synthetic saponins

et al. 2020

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Section: Rsc Medicinal Chemistrymentioning

confidence: 99%

An investigation of the antileishmanial properties of semi-synthetic saponins

et al. 2020

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“…High‐throughput screening (HTS) is a typical method to determine drug candidates from huge libraries of potentially active compounds. There is growing interest in exploiting S. cerevisiae for new HTS tasks and particularly in antimalaria research (Denny, ; Williams et al, ). The idea of using purine metabolism as a target for antiparasitic drugs is appealing due to the fact that the parasite relies exclusively on the host for its purine supply and as its purine uptake mechanism is distinct from that of the host (review in el Kouni, , Frame, Deniskin, Arora, & Akabas, ).…”

Section: Applications Of Purine Auxotrophic Yeastmentioning

confidence: 99%

“…There is growing interest in exploiting S. cerevisiae for new HTS tasks and particularly in antimalaria research (Denny, 2018;Williams et al, 2015). The idea of using purine metabolism as a target for antiparasitic drugs is appealing due to the fact that the parasite relies exclusively on the host for its purine supply and as its purine uptake mechanism is distinct from that of the host ( culture and proved to be highly active .…”

Section: Applications Of Purine Auxotrophic Yeastmentioning

confidence: 99%

Purine auxotrophy: Possible applications beyond genetic marker

Kokina

Ozoliņa

Liepiņš

2019

Yeast

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Exploring new drug candidates or drug targets against many illnesses is necessary as “traditional” treatments lose their effectivity. Cancer and sicknesses caused by protozoan parasites are among these diseases. Cell purine metabolism is an important drug target. Theoretically, inhibiting purine metabolism could stop the proliferation of unwanted cells. Purine metabolism is similar across all eukaryotes. However, some medically important organisms or cell lines rely on their host purine metabolism. Protozoans causing malaria, leishmaniasis, or toxoplasmosis are purine auxotrophs. Some cancer forms have also lost the ability to synthesize purines de novo. Budding yeast can serve as an effective model for eukaryotic purine metabolism, and thus, purine auxotrophic strains could be an important tool. In this review, we present the common principles of purine metabolism in eukaryotes, effects of purine starvation in eukaryotic cells, and purine‐starved Saccharomyces cerevisiae as a model for purine depletion‐elicited metabolic states with applications in evolution studies and pharmacology. Purine auxotrophic yeast strains behave differently when growing in media with sufficient supplementation with adenine or in media depleted of adenine (starvation). In the latter, they undergo cell cycle arrest at G1/G0 and become stress resistant. Importantly, similar effects have also been observed among parasitic protozoans or cancer cells. We consider that studies on metabolic changes caused by purine auxotrophy could reveal new options for parasite or cancer therapy. Further, knowledge on phenotypic changes will improve the use of auxotrophic strains in high‐throughput screening for primary drug candidates.

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“…This assay is efficient, requires little time and small amounts of the compound, while it is adaptable to a high-throughput platform and yields data that accurately and reproducibly detect DNA damage based on metabolic activation. Furthermore, the use of genetically tractable model yeast as a vehicle for target-based high-throughput screening has overcome numerous limitations of in vitro biochemical and phenotypic assay platforms for drug discovery by allowing the identification of on-target compounds that function within a eukaryotic cellular context (26).…”

Section: Discussionmentioning

confidence: 99%

Potential use of Pichia pastoris strain SMD1168H expressing DNA topoisomerase I in the screening of potential anti‑breast cancer agents

et al. 2019

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Cancer chemotherapy possesses high toxicity, particularly when a higher concentration of drugs is administered to patients. Therefore, searching for more effective compounds to reduce the toxicity of treatments, while still producing similar effects as current chemotherapy regimens, is required. Currently, the search for potential anticancer agents involves a random, inaccurate process with strategic deficits and a lack of specific targets. For this reason, the initial in vitro high-throughput steps in the screening process should be reviewed for rapid identification of the compounds that may serve as anticancer agents. The present study aimed to investigate the potential use of the Pichia pastoris strain SMD1168H expressing DNA topoisomerase I (SMD1168H-TOPOI) in a yeast-based assay for screening potential anticancer agents. The cell density that indicated the growth of the recombinant yeast without treatment was first measured by spectrophotometry. Subsequently, the effects of glutamate (agonist) and camptothecin (antagonist) on the recombinant yeast cell density were investigated using the same approach, and finally, the effect of camptothecin on various cell lines was determined and compared with its effect on recombinant yeast. The current study demonstrated that growth was enhanced in SMD1168H-TOPOI as compared with that in SMD1168H. Glutamate also enhanced the growth of the SMD1168H; however, the growth effect was not enhanced in SMD1168H-TOPOI treated with glutamate. By contrast, camptothecin caused only lower cell density and growth throughout the treatment of SMD1168H-TOPOI. The findings of the current study indicated that SMD1168H-TOPOI has similar characteristics to MDA-MB-231 cells; therefore, it can be used in a yeast-based assay to screen for more effective compounds that may inhibit the growth of highly metastatic breast cancer cells.

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Yeast: bridging the gap between phenotypic and biochemical assays for high-throughput screening

Cited by 19 publications

References 54 publications

An investigation of the antileishmanial properties of semi-synthetic saponins

An investigation of the antileishmanial properties of semi-synthetic saponins

Purine auxotrophy: Possible applications beyond genetic marker

Potential use of Pichia pastoris strain SMD1168H expressing DNA topoisomerase I in the screening of potential anti‑breast cancer agents

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