Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs
| العنوان: | Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs |
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| المؤلفون: | Eva Rico, Andrew W. Pountain, Isabel M. Vincent, Michael J. Witty, Michael P. Barrett, Fernando Fernandez-Cortes, Ning Zhang, Mark C. Field, David Horn, Jonathan M. Wilkes, Justin J. J. van der Hooft, Yvonne Freund, Darren Y. Edwards, Daniel Paape, Liam J. Morrison, Rosemary Peter, Clément Regnault, Federica Giordani, Kevin D. Read |
| المصدر: | PLoS Pathogens, Vol 16, Iss 11, p e1008932 (2020) PLoS Pathogens PLoS Pathogens, 16(11) PLoS Pathogens 16 (2020) 11 Giordani, F, Paape, D, Vincent, I M, Pountain, A W, Fernandez-Cortes, F, Rico, E, Zhang, N, Morrison, L, Freund, Y, Witty, M J, Peter, R, Edwards, D, Wilkes, J, van der Hooft, J J J, Regnault, C, Read, K D, Horn, D, Field, M C & Barrett, M P 2020, ' Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs ', PLoS Pathogens, vol. 16, no. 11, e1008932 . https://doi.org/10.1371/journal.ppat.1008932 |
| بيانات النشر: | Public Library of Science (PLoS), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Benzoxaborole, Veterinary medicine, Trypanosoma congolense, Carboxylic Acids, Drug Resistance, Protozoan Proteins, Drug resistance, Carboxypeptidases, Parasitemia, Biochemistry, Serine, Mice, RNA interference, Prodrugs, Trypanosoma brucei, Amino Acids, Biology (General), 2. Zero hunger, Protozoans, 0303 health sciences, biology, Chemistry, Organic Compounds, Eukaryota, Valine, Genomics, Prodrug, Trypanocidal Agents, 3. Good health, Nucleic acids, Genetic interference, Physical Sciences, Epigenetics, Female, prodrug, Research Article, Boron Compounds, Trypanosoma, Livestock, Bioinformatics, QH301-705.5, Immunology, Trypanosoma brucei brucei, Research and Analysis Methods, Microbiology, 03 medical and health sciences, Virology, Hydroxyl Amino Acids, Bioinformatica, parasitic diseases, Trypanosoma Brucei, Genetics, Life Science, Animals, nagana, Trypanosoma vivax, Molecular Biology Techniques, Gene, Molecular Biology, 030304 developmental biology, animal African trypanosomiasis, drug resistance, 030306 microbiology, veterinary trypanocide, Organic Chemistry, Organisms, Chemical Compounds, Biology and Life Sciences, Proteins, RC581-607, biology.organism_classification, Carboxypeptidase, Parasitic Protozoans, Trypanosomiasis, African, biology.protein, RNA, Parasitology, Gene expression, Immunologic diseases. Allergy, Trypanosoma Brucei Gambiense, Cloning |
| الوصف: | 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. Author summary AN11736 is a member of the benzoxaborole class identified as a development candidate for animal African trypanosomiasis, a deadly livestock disease with huge economic impact. As part of its early evaluation phase, we set to unravel the risk and mode of resistance to this new trypanocide. We discovered that AN11736 behaves as a prodrug that, once inside trypanosomes, is cleaved by the activity of specific serine carboxypeptidases. AN11736-resistant Trypanosoma brucei and T. congolense had deletions within the serine carboxypeptidase gene array, resulting in their being unable to efficiently process the parent drug. Other benzoxaboroles with a similar sub-structure are also substrates for the serine carboxypeptidases, hence our findings assume great importance in considering the future development and deployment of this class of compounds. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1553-7374 1553-7366 1553-7390 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f1a3504630182edfb682742da45095c8 https://doaj.org/article/a5d1aac4a0fd47b29679ea476bd015f8 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....f1a3504630182edfb682742da45095c8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15537374 15537366 15537390 |
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