Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs

Livestock diseases caused by Trypanosoma congolense , T . vivax and T . brucei , collectively known as nagana, are responsible for billions of dollars in lost food production annually. There is an urgent need for novel therapeutics. Encouragingly, promising antitrypanosomal benzoxaboroles are under...

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Veröffentlicht in:	PLoS pathogens Jg. 16; H. 11; S. e1008932
Hauptverfasser:	Giordani, Federica, Paape, Daniel, Vincent, Isabel M., Pountain, Andrew W., Fernández-Cortés, Fernando, Rico, Eva, Zhang, Ning, Morrison, Liam J., Freund, Yvonne, Witty, Michael J., Peter, Rosemary, Edwards, Darren Y., Wilkes, Jonathan M., van der Hooft, Justin J. J., Regnault, Clément, Read, Kevin D., Horn, David, Field, Mark C., Barrett, Michael P.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States Public Library of Science 03.11.2020 Public Library of Science (PLoS)
Schlagworte:	Aldehyde dehydrogenase Aldehydes Analysis Animals Biology and Life Sciences Boron Compounds - metabolism Carboxylic Acids - metabolism Carboxypeptidase Carboxypeptidases - metabolism Chemical compounds Chemical properties Chromosome 10 Chromosomes Cloning Dosage and administration Drug dosages Drug Resistance Drug therapy Drugs Enzyme activation Female Forecasts and trends Gene sequencing Genes Genomes Identification and classification Infectious diseases Influence Livestock Metabolism Metabolomics Methionine Methylation Mice Nucleotide sequence Parasitemia - veterinary Parasites Peptidase Peptidases Peptides Physical Sciences Prodrugs Prodrugs - metabolism Proteases Protozoan Proteins - metabolism Research and Analysis Methods RNA processing Serine Serine carboxypeptidase Splicing Synteny Trypanocidal Agents - metabolism Trypanosoma Trypanosoma brucei brucei - drug effects Trypanosoma brucei brucei - enzymology Trypanosoma congolense - drug effects Trypanosoma congolense - enzymology Trypanosoma vivax - drug effects Trypanosoma vivax - enzymology Trypanosomiasis, African - drug therapy Trypanosomiasis, African - parasitology Trypanosomiasis, African - veterinary Valine - analogs & derivatives Valine - metabolism Veterinary research Whole genome sequencing United Kingdom
ISSN:	1553-7374, 1553-7366, 1553-7374
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Zusammenfassung:	Livestock diseases caused by Trypanosoma congolense , T . vivax and T . brucei , collectively known as nagana, are responsible for billions of dollars in lost food production annually. There is an urgent need for novel therapeutics. Encouragingly, promising antitrypanosomal benzoxaboroles are under veterinary development. Here, we show that the most efficacious subclass of these compounds are prodrugs activated by trypanosome serine carboxypeptidases (CBPs). Drug-resistance to a development candidate, AN11736, emerged readily in T . brucei , due to partial deletion within the locus containing three tandem copies of the CBP genes. T . congolense parasites, which possess a larger array of related CBPs , also developed resistance to AN11736 through deletion within the locus. A genome-scale screen in T . brucei confirmed CBP loss-of-function as the primary mechanism of resistance and CRISPR-Cas9 editing proved that partial deletion within the locus was sufficient to confer resistance. CBP re-expression in either T . brucei or T . congolense AN11736-resistant lines restored drug-susceptibility. CBPs act by cleaving the benzoxaborole AN11736 to a carboxylic acid derivative, revealing a prodrug activation mechanism. Loss of CBP activity results in massive reduction in net uptake of AN11736, indicating that entry is facilitated by the concentration gradient created by prodrug metabolism.
Bibliographie:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 The authors have declared that no competing interests exist.
ISSN:	1553-7374 1553-7366 1553-7374
DOI:	10.1371/journal.ppat.1008932