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Genome-scale RNA interference profiling of Trypanosoma brucei sensitivity determinants for experimental phthalimide-based trypanocidal drug PHT-39

ABSTRACT: Genome-scale RNA interference profiling of Trypanosoma brucei sensitivity determinants for experimental phthalimide-based trypanocidal drug PHT-39

PROVIDER: PRJEB72905 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR12688287_1.fastq.gz	Fastqsanger.gz
	ERR12688287_2.fastq.gz	Fastqsanger.gz

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Genome-scale RNA interference profiling of Trypanosoma brucei sensitivity determinants for experimental phthalimide-based trypanocidal drug PHT-39

Project description:In a phenotypic screening approach of novel molecules composed of a synergistic combination of phthalimide, benzimidazole, and triazole scaffolds we discovered compounds with potent anti-leishmanial activity. The resulting early-lead compound PHT-39, which contains a trifluoromethyl substitution, demonstrated the highest efficacy in a Leishmania infantum intramacrophage assay, with an EC50 of 1.2+/- 3.2 μM.Cytotoxicity testing of PHT-39 in Hep-G2 cells indicated high selectivity of over 90-fold. To investigate the mechanism of action we carried out experiments in Trypanosoma brucei, which is also sensitive to PHT-39. Here we used a genome-wide RNAi library approach (PMID: 22278056; PMID: 21363968) to detect sensitivity determinants. This high-throughput phenotyping approach identified sensitivity determinants for PHT-39, which included a P-type ATPase that is crucial for the uptake of miltefosine and amphotericin, strongly indicating a shared route for cellular entry.

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In vivo RNA interference RNAi target sequencing of Trypanosoma brucei

Project description:A direct comparison of RNAi in vitro with RNAi in vivo is being performed using RNA interference (RNAi) target sequencing (RIT-Seq) of Trypanosoma brucei to identify all genes specifically required for growth in vivo (the infectome). Assembly of the bloodstream-form T. brucei RNAi library and the RNAi target sequencing (RIT-seq) approach in African trypanosomes were reported previously in Alsford, S. et al. High-throughput phenotyping using parallel sequencing of RNA interference targets in the African trypanosome. Genome Res 21, 915-924, 264 doi:gr.115089.110 [pii] 265 10.1101/gr.115089.110 (2011) and Alsford,S et al. High-throughput decoding of antitrypanosomal drug efficacy and resistance. Nature 482, 232236 doi:10.1038/nature10771 (2012). This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

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