ArticlePLoS pathogens2020
Veterinary trypanocidal benzoxaboroles are peptidase-activated prodrugs.
Article in PLoS pathogens, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
What it found
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Who cites it
17 citing papers in PubMed, 32 citations in OpenAlex.
- Comparative lipidomic profiling of African trypanosomes reveals metabolic distinctions impacting pan-species drug development.PLoS neglected tropical diseases · 2026Article
- A cell surface transporter mediates phenanthridine resistance in African trypanosomes.npj antimicrobials and resistance · 2026Article
- Recent Advancements in the Diversification and Applications of Boron-Containing Compounds in Medicinal Chemistry.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Cure of experimentalmBio · 2025Article
- Interventions for Neglected Diseases Caused by Kinetoplastid Parasites: A One Health Approach to Drug Discovery, Development, and Deployment.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Longitudinal observational (single cohort) study on the causes of trypanocide failure in cases of African animal trypanosomosis in cattle near wildlife protected areas of Northern Tanzania.PLoS neglected tropical diseases · 2025Article
- Article
- Drug resistance in animal trypanosomiases: Epidemiology, mechanisms and control strategies.International journal for parasitology. Drugs and drug resistance · 2024Review
- New Lipophilic Hydroxamates as Promising Trypanocidal Agents: Design, Synthesis, SAR, and Conformational Behavior Studies.ACS medicinal chemistry letters · 2024Article
- Novel Lipophilic Hydroxamates Based on Spirocarbocyclic Hydantoin Scaffolds with Potent Antiviral and Trypanocidal Activity.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Targeting trypanosomes: how chemogenomics and artificial intelligence can guide drug discovery.Biochemical Society transactions · 2023Review
- Clinically relevant benzoxaboroles inhibit mRNA processing in Trypanosoma brucei.BMC research notes · 2022Article
- Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates.Nature microbiology · 2022Article
- Differences in Transporters Rather than Drug Targets Are the Principal Determinants of the Different Innate Sensitivities ofInternational journal of molecular sciences · 2022Article
- Comparative Sensitivity and Specificity of the 7SL sRNA Diagnostic Test for Animal Trypanosomiasis.Frontiers in veterinary science · 2022Article
- Transcriptional differentiation of Trypanosoma brucei during in vitro acquisition of resistance to acoziborole.PLoS neglected tropical diseases · 2021Article
- Identification of Resistance Determinants for a Promising Antileishmanial Oxaborole Series.Microorganisms · 2021Article
Corrections and comments
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Authors and funding
19 authors at 5 institutions in 3 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.