Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
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 |
| Zdroj: | 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 |
| ISSN: | 1553-7374 1553-7366 1553-7390 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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