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Your search keyword '"Flannery, EL"' showing total 2 results
Start Over Author "Flannery, EL" Publisher american association for the advancement of science
2 results on '"Flannery, EL"'

1. Validation of the protein kinase Pf CLK3 as a multistage cross-species malarial drug target.

Author

Alam MM, Sanchez-Azqueta A, Janha O, Flannery EL, Mahindra A, Mapesa K, Char AB, Sriranganadane D, Brancucci NMB, Antonova-Koch Y, Crouch K, Simwela NV, Millar SB, Akinwale J, Mitcheson D, Solyakov L, Dudek K, Jones C, Zapatero C, Doerig C, Nwakanma DC, Vázquez MJ, Colmenarejo G, Lafuente-Monasterio MJ, Leon ML, Godoi PHC, Elkins JM, Waters AP, Jamieson AG, Álvaro EF, Ranford-Cartwright LC, Marti M, Winzeler EA, Gamo FJ, and Tobin AB

Subjects
Animals, Antimalarials chemistry, Antimalarials isolation & purification, Antimalarials therapeutic use, Gametogenesis drug effects, High-Throughput Screening Assays, Mice, Mice, Inbred BALB C, Plasmodium falciparum enzymology, Plasmodium falciparum genetics, Protein Kinase Inhibitors isolation & purification, Protein Kinase Inhibitors therapeutic use, Protein Serine-Threonine Kinases genetics, Protein-Tyrosine Kinases genetics, Protozoan Proteins genetics, RNA Splicing genetics, Small Molecule Libraries pharmacology, Antimalarials pharmacology, Molecular Targeted Therapy, Plasmodium falciparum drug effects, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases antagonists & inhibitors, Protozoan Proteins antagonists & inhibitors
Abstract

The requirement for next-generation antimalarials to be both curative and transmission-blocking necessitates the identification of previously undiscovered druggable molecular pathways. We identified a selective inhibitor of the Plasmodium falciparum protein kinase Pf CLK3, which we used in combination with chemogenetics to validate Pf CLK3 as a drug target acting at multiple parasite life stages. Consistent with a role for Pf CLK3 in RNA splicing, inhibition resulted in the down-regulation of more than 400 essential parasite genes. Inhibition of Pf CLK3 mediated rapid killing of asexual liver- and blood-stage P. falciparum and blockade of gametocyte development, thereby preventing transmission, and also showed parasiticidal activity against P. berghei and P. knowlesi Hence, our data establish Pf CLK3 as a target for drugs, with the potential to offer a cure-to be prophylactic and transmission blocking in malaria., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Published
2019
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2. Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics.

Author

Cowell AN, Istvan ES, Lukens AK, Gomez-Lorenzo MG, Vanaerschot M, Sakata-Kato T, Flannery EL, Magistrado P, Owen E, Abraham M, LaMonte G, Painter HJ, Williams RM, Franco V, Linares M, Arriaga I, Bopp S, Corey VC, Gnädig NF, Coburn-Flynn O, Reimer C, Gupta P, Murithi JM, Moura PA, Fuchs O, Sasaki E, Kim SW, Teng CH, Wang LT, Akidil A, Adjalley S, Willis PA, Siegel D, Tanaseichuk O, Zhong Y, Zhou Y, Llinás M, Ottilie S, Gamo FJ, Lee MCS, Goldberg DE, Fidock DA, Wirth DF, and Winzeler EA

Subjects
Activation, Metabolic, Alleles, DNA Copy Number Variations, Directed Molecular Evolution, Drug Resistance, Multiple genetics, Genes, Protozoan, Metabolomics, Mutation, Plasmodium falciparum growth & development, Selection, Genetic, Transcription Factors chemistry, Transcription Factors genetics, Transcription Factors metabolism, Antimalarials pharmacology, Drug Resistance genetics, Genome, Protozoan, Plasmodium falciparum drug effects, Plasmodium falciparum genetics
Abstract

Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previously identified multidrug-resistance mechanisms, we discovered hitherto unrecognized drug target-inhibitor pairs, including thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This exploration of the P. falciparum resistome and druggable genome will likely guide drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms available to the malaria parasite., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Published
2018
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