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BioAssay: AID 504696

Summary Assay for small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate

Tropical malaria caused by the protozoan parasite Plasmodium falciparum is responsible for up to three million deaths annually. Due to increasing regional distribution and resistances against the clinically used antimalarials, novel antimalarial drugs - which have new mechanisms of action and are suitable for combination therapies - are urgently required. Plasmodium falciparum Glucose-6-phosphate more ..
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AID: 504696
Data Source: Burnham Center for Chemical Genomics (SBCCG-A640-pfG6PDH-Summary-Assay)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2011-04-22
Modify Date: 2011-05-17
Target
Depositor Specified Assays
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AIDNameTypeComment
504690uHTS identification of small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate dehydrogenase via a fluorescence intensity assayscreeningPrimary Screen
504753Single concentration confirmation of uHTS small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate dehydrogenase via a fluorescence intensity assayscreening
504765Dose Response confirmation of uHTS small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate dehydrogenase via a fluorescence intensity assayconfirmatory
504792Human Glucose-6-Phosphate Dehydrogenase Dose Response Selectivity Assay for Inhibitors of Plasmodium falciparum Glucose-6-Phosphate Dehydrogenaseconfirmatory
504862uHTS Identification of Diaphorase Inhibitors and Chemical Oxidizers: Counter Screen for the uHTS identification of small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate dehydrogenase via a fluorescence intensity assay in the presence of 10 uM NADPHscreening
504863uHTS Identification of Diaphorase Inhibitors and Chemical Oxidizers: Counter Screen for the uHTS identification of small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate dehydrogenase via a fluorescence intensity assay in the presence of 30 uM NADPHscreening
540252Dose Response orthogonal assay utilizing the direct end-point detection of NADPH for uHTS small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate dehydrogenaseconfirmatory
540269Dose Response orthogonal kinetic assay utilizing the direct detection of NADPH for uHTS small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate dehydrogenaseconfirmatory
588414SAR analysis of small molecule inhibitors of Plasmodium falciparum Glucose-6-Phosphate Dehydrogenase using a Human Glucose-6-Phosphate Dehydrogenase Dose Response Selectivity Assayconfirmatory
588415SAR analysis of small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate dehydrogenase via a fluorescence intensity assayconfirmatory
588588SAR analysis of small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate dehydrogenase in an orthogonal assay utilizing the direct end-point detection of NADPHconfirmatory
588593SAR analysis of small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate dehydrogenase in an orthogonal kinetic assay utilizing the direct detection of NADPHconfirmatory
588671SAR analysis of small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate dehydrogenase via a fluorescence intensity assay - Set 2confirmatory
588672SAR analysis of small molecule inhibitors of Plasmodium falciparum Glucose-6-Phosphate Dehydrogenase using a Human Glucose-6-Phosphate Dehydrogenase Dose Response Selectivity Assay - Set 2confirmatory
602130SAR analysis of small molecule inhibitors of Plasmodium falciparum Glucose-6-Phosphate Dehydrogenase using a Human Glucose-6-Phosphate Dehydrogenase Dose Response Selectivity Assay - Set 3confirmatory
602131SAR analysis of small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate dehydrogenase via a fluorescence intensity assay - Set 3confirmatory
602132SAR analysis of small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate dehydrogenase in an orthogonal assay utilizing the direct end-point detection of NADPH - Set 2confirmatory
602133SAR analysis of small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate dehydrogenase in an orthogonal kinetic assay utilizing the direct detection of NADPH - Set 2confirmatory
602423SAR analysis of small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate dehydrogenase via a fluorescence intensity assay - Set 4confirmatory
602424SAR analysis of small molecule inhibitors of Plasmodium falciparum Glucose-6-Phosphate Dehydrogenase using a Human Glucose-6-Phosphate Dehydrogenase Dose Response Selectivity Assay - Set 4confirmatory
602425SAR analysis of small molecule inhibitors of Plasmodium falciparum Glucose-6-phosphate dehydrogenase in an orthogonal kinetic assay utilizing the direct detection of NADPH - Set 3confirmatory
Description:
Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG)
Source Affiliation: Sanford-Burnham Medical Research Institute (SBMRI, San Diego CA)
Network: NIH Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Number: 1R21AI082434-01
Assay Provider: Lars Bode, Ph.D., University of California San Diego, San Diego, CA

Tropical malaria caused by the protozoan parasite Plasmodium falciparum is responsible for up to three million deaths annually. Due to increasing regional distribution and resistances against the clinically used antimalarials, novel antimalarial drugs - which have new mechanisms of action and are suitable for combination therapies - are urgently required. Plasmodium falciparum Glucose-6-phosphate dehydrogenase (PfGluPho) is a potential novel target for antimalarial drug design. Glucose-6-Phosphate Dehydrogenase (G6PD) reaction is the first and rate-limiting step in the pentose phosphate pathway (PPP), catalyzed by a bifunctional enzyme Plasmodium falciparum Glucose-6-phosphate dehydrogenase-6-Phosphogluconolactonase (PfGluPho) catalyzing the first two steps of the PPP, a key metabolic pathway sustaining anabolic needs in reductive equivalents and synthetic materials in fast-growing cells. Plasmodium falciparum cells and infected host RBCs rely on accelerated glucose flux and are dependent on glucose-6-phopshate dehydrogenase activity of PfGluPho. The parasite enzyme is essential for plasmodium proliferation and it differs structurally and mechanistically from the human enzyme, thus making it an excellent target for novel antimalarial drug design. Prior to this study PfGluPho protein was unavailable and its selective and specific inhibitors are non-existent. Given this gap, our rationale in developing a HTS screen is to find chemical probes that inhibit Plasmodium G6PD activity that might lead to novel anti-malarial therapies.

Glucose-6-Phosphate Dehydrogenase (G6PD), an enzyme that converts Glucose-6-Phosphate to 6-Phosphoglucono-delta-lactone, is the first and rate-limiting step of the Pentose Phosphate Pathway (PPP), one of the key pathways for glucose metabolism in most cells. The activity of G6PD determines whether glucose is metabolized through glycolysis or the PPP. In contrast to glycolysis, the primary role of the PPP is anabolic rather than catabolic, providing NADPH for the biosynthesis of fatty acids and cholesterol, as well as Ribose-5-Phosphate as the precursor for the synthesis of nucleotides and nucleic acids, which is especially important for rapidly growing plasmodium cells. Parasite and plasmodium-infected host cells demonstrate elevated rates of glucose consumption comparing to uninfected red blood cells.
Protocol
Please see pertinent AIDs: 504690
Comment
Probe molecules are defined as the positives of this assay and assigned a score of 100. Testing has not progressed to the point where a probe molecule has been identified.
Additional Information
Grant Number: 1R21AI082434-01

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