ArticlePLoS pathogens2018
The trypanocidal benzoxaborole AN7973 inhibits trypanosome mRNA processing.
Article in PLoS pathogens, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed.
- On the mode of anti-Future science OA · 2026Article
- Integrating Molecular Similarity and AlphaFold-Based Structural Alignment for Target Discovery inPharmaceuticals (Basel, Switzerland) · 2026Article
- Acoziborole resistance associated mutations in Trypanosoma brucei CPSF3.PLoS pathogens · 2026Article
- A Novel Class of Orally Bioavailable Phenylglycine-Benzoxaborole Conjugates with Antimalarial Activity and Potentially Novel Mechanism of Action.ACS medicinal chemistry letters · 2026Article
- Advances and challenges in the search for new treatments for Chagas disease.Memorias do Instituto Oswaldo Cruz · 2026Review
- Recent Advancements in the Diversification and Applications of Boron-Containing Compounds in Medicinal Chemistry.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Transforming the chemotherapy of human African trypanosomiasis.Clinical microbiology reviews · 2025Review
- Structural basis of Spliced Leader RNA recognition by the Trypanosoma brucei cap-binding complex.Nature communications · 2025Article
- Targeting RNA-binding proteins with small molecules: perspectives and challenges.Frontiers in chemistry · 2025Review
- Multiparameter ranking of carbazoles for anti-trypanosome lead discovery.Frontiers in drug discovery · 2024Article
- The anticancer compound JTE-607 reveals hidden sequence specificity of the mRNA 3' processing machinery.Nature structural & molecular biology · 2023Article
- The critical role of mode of action studies in kinetoplastid drug discovery.Frontiers in drug discovery · 2023Article
- The pipeline for drugs for control and elimination of neglected tropical diseases: 1. Anti-infective drugs for regulatory registration.Parasites & vectors · 2023Review
- Comparative genomics and interactomics of polyadenylation factors for the prediction of new parasite targets: Entamoeba histolytica as a working model.Bioscience reports · 2023Article
- Clinically relevant benzoxaboroles inhibit mRNA processing in Trypanosoma brucei.BMC research notes · 2022Article
- Hypothesis-generating proteome perturbation to identify NEU-4438 and acoziborole modes of action in the African Trypanosome.iScience · 2022Article
- Sending the message: specialized RNA export mechanisms in trypanosomes.Trends in parasitology · 2022Review
- Discovery of an orally active benzoxaborole prodrug effective in the treatment of Chagas disease in non-human primates.Nature microbiology · 2022Article
- Sequences and proteins that influence mRNA processing in Trypanosoma brucei: Evolutionary conservation of SR-domain and PTB protein functions.PLoS neglected tropical diseases · 2022Article
- TheRNA (New York, N.Y.) · 2022Article
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12 authors.
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Abstract
Kinetoplastid parasites-trypanosomes and leishmanias-infect millions of humans and cause economically devastating diseases of livestock, and the few existing drugs have serious deficiencies. Benzoxaborole-based compounds are very promising potential novel anti-trypanosomal therapies, with candidates already in human and animal clinical trials. We investigated the mechanism of action of several benzoxaboroles, including AN7973, an early candidate for veterinary trypanosomosis. In all kinetoplastids, transcription is polycistronic. Individual mRNA 5'-ends are created by trans splicing of a short leader sequence, with coupled polyadenylation of the preceding mRNA. Treatment of Trypanosoma brucei with AN7973 inhibited trans splicing within 1h, as judged by loss of the Y-structure splicing intermediate, reduced levels of mRNA, and accumulation of peri-nuclear granules. Methylation of the spliced leader precursor RNA was not affected, but more prolonged AN7973 treatment caused an increase in S-adenosyl methionine and methylated lysine. Together, the results indicate that mRNA processing is a primary target of AN7973. Polyadenylation is required for kinetoplastid trans splicing, and the EC50 for AN7973 in T. brucei was increased three-fold by over-expression of the T. brucei cleavage and polyadenylation factor CPSF3, identifying CPSF3 as a potential molecular target. Molecular modeling results suggested that inhibition of CPSF3 by AN7973 is feasible. Our results thus chemically validate mRNA processing as a viable drug target in trypanosomes. Several other benzoxaboroles showed metabolomic and splicing effects that were similar to those of AN7973, identifying splicing inhibition as a common mode of action and suggesting that it might be linked to subsequent changes in methylated metabolites. Granule formation, splicing inhibition and resistance after CPSF3 expression did not, however, always correlate and prolonged selection of trypanosomes in AN7973 resulted in only 1.5-fold resistance. It is therefore possible that the modes of action of oxaboroles that target trypanosome mRNA processing might extend beyond CPSF3 inhibition.
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