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BioAssay: AID 624155

qHTS of Trypanosoma Brucei Inhibitors: Summary

Members of the Trypanosomatidae family of parasitic protozoans cause a spectrum of diseases throughout the tropical and subtropical world. Sleeping sickness, caused by two subspecies of Trypanosoma brucei, is endemic to areas of sub-Saharan Africa, while Chagas' disease, a manifestation of Trypanosoma cruzi infection, is prevalent throughout Central and South America. In addition, many species more ..
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AID: 624155
Data Source: NCGC (TbPyK000)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2012-05-16
Target
Related Experiments
AIDNameTypeComment
624147qHTS of Trypanosoma Brucei Inhibitors: LOPAC ValidationConfirmatorydepositor-specified cross reference
624173qHTS of Trypanosoma Brucei InhibitorsConfirmatorydepositor-specified cross reference
720569qHTS of Trypanosoma Brucei Inhibitors: Confirmatory Assay for Cherry-picked CompoundsConfirmatorydepositor-specified cross reference
720584qHTS of Trypanosoma Brucei Inhibitors: Orthogonal Assay for Cherry-picked CompoundsConfirmatorydepositor-specified cross reference
Description:
Members of the Trypanosomatidae family of parasitic protozoans cause a spectrum of diseases throughout the tropical and subtropical world. Sleeping sickness, caused by two subspecies of Trypanosoma brucei, is endemic to areas of sub-Saharan Africa, while Chagas' disease, a manifestation of Trypanosoma cruzi infection, is prevalent throughout Central and South America. In addition, many species of Leishmania are responsible for a range of cutaneous and visceral diseases, causing ulcers, destructive lesions and kalaazar, a lethal infection of the viscera. These diseases cause severe public health and economic burdens on populations that are often already caught in a tragic cycle of poverty, poor nutrition and disease. Collectively, parasites of the trypanosomatid family infect 30 million people worldwide (~500 million live in endemic areas), and account for ~130K deaths annually. Existing treatments have developed little in the past 50 years, and suffer from toxicity, poor efficacy and resistance; the goal of this project is to develop lead drugs that will be suitable for entry into pre-clinical trials.

This project will build on previous work that has demonstrated carbohydrate metabolism to be a strong drug target in trypanosomatids. {Verlinde, 2001} Blood-stream or infective stages of T. brucei are entirely dependent on glycolysis as a source of ATP, because the tricarboxylic acid cycle and oxidative phosphorylation are both repressed. Glycolysis in axenically cultured T. cruzi, representing the intracellular pathogenic stage, is also essential for these parasites. {Engel, 1987} This project aims to discover and optimize selective inhibitors of the glycolytic enzyme pyruvate kinase (PYK) from Trypanosoma brucei, the parasite that causes sleeping sickness. TbPYK has been validated as a drug target by RNAi where RNAi knockdown of PYK in T. brucei was found to be lethal to cultured parasites, with a 50% reduction in glycolytic flux sufficient to kill the cells.{Albert, 2005} Detailed structural information for PYK is available. Trypanosomatid PYKs show significant differences from their human counterparts including only 47-50% sequence identity and different allosteric and activation properties.{Callens, 1992} To this end, a qHTS was done against the MLSMR to discover inhibitors.

NIH Molecular Libraries Probe Production Network [MLPCN]
NIH Chemical Genomics Center [NCGC]

Grant: MH095452
PI Name: Malcolm Walkinshaw, University of Edinburgh
Protocol
Please see linked AIDs for detailed protocols.
Comment
This project is on-going and will be updated at a later point.
Additional Information
Grant Number: MH095452

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