Key result
Acoziborole and AN11736 inhibit Trypanosoma brucei mRNA processing, disrupting spliced and polycistronic transcripts.
Why the study?
The effects of benzoxaborole drug candidates acoziborole and AN11736 on mRNA processing in Trypanosoma brucei were not fully characterized.
Supports benzoxaborole development for trypanosomiasis; leaves open precise target and clinical translation.
Objective The cleavage and polyadenylation endonuclease CPSF73 is thought to be the target of the anti-trypanosomal benzoxaboroles AN7973, acoziborole and AN11736. We previously showed that AN7973 inhibits mRNA processing. We here investigated whether the drug candidates acoziborole (for human sleeping sickness) and AN11736 (for nagana in cattle) have same effect. We also affinity purified tagged CPSF73 from parasites without, or after, AN7973 treatment, and analysed differentially co-purified proteins my mass spectrometry. Results AN11736 and acoziborole both inhibited mRNA processing, as demonstrated by decreased levels of spliced mRNAs and accumulation of di- and tri-cistronic mRNAs from the alpha-beta tubulin locus. Treating the cells with AN7973 did not significantly affect the proteins that copurified with CPSF73.
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Waithaka et al. (2022) studied African trypanosomiasis. Acoziborole and AN11736 vs. Untreated cells was evaluated on Inhibition of mRNA processing (levels of spliced mRNAs and accumulation of polycistronic mRNAs). Acoziborole and AN11736 inhibit mRNA processing in Trypanosoma brucei, evidenced by decreased spliced mRNAs and accumulation of di- and tri-cistronic mRNAs.
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