Your browser doesn't support javascript.
loading
Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs.
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.
Afiliación
  • Giordani F; Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
  • Paape D; Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
  • Vincent IM; Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
  • Pountain AW; Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
  • Fernández-Cortés F; Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
  • Rico E; Wellcome Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
  • Zhang N; Wellcome Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
  • Morrison LJ; Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, United Kingdom.
  • Freund Y; Anacor Pharmaceuticals, Inc., Palo Alto, California, United States of America.
  • Witty MJ; Global Alliance for Livestock and Veterinary Medicine, Pentlands Science Park, Penicuik, Edinburgh, United Kingdom.
  • Peter R; Global Alliance for Livestock and Veterinary Medicine, Pentlands Science Park, Penicuik, Edinburgh, United Kingdom.
  • Edwards DY; Wellcome Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
  • Wilkes JM; Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
  • van der Hooft JJJ; Glasgow Polyomics, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
  • Regnault C; Current address: Bioinformatics Group, Wageningen University, Wageningen, the Netherlands.
  • Read KD; Glasgow Polyomics, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
  • Horn D; Wellcome Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
  • Field MC; Wellcome Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
  • Barrett MP; Wellcome Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
PLoS Pathog ; 16(11): e1008932, 2020 11.
Article en En | MEDLINE | ID: mdl-33141865
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.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tripanocidas / Trypanosoma brucei brucei / Tripanosomiasis Africana / Valina / Compuestos de Boro / Trypanosoma congolense / Carboxipeptidasas / Trypanosoma vivax Límite: Animals Idioma: En Revista: PLoS Pathog Año: 2020 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tripanocidas / Trypanosoma brucei brucei / Tripanosomiasis Africana / Valina / Compuestos de Boro / Trypanosoma congolense / Carboxipeptidasas / Trypanosoma vivax Límite: Animals Idioma: En Revista: PLoS Pathog Año: 2020 Tipo del documento: Article País de afiliación: Reino Unido Pais de publicación: Estados Unidos