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Clinically relevant benzoxaboroles inhibit mRNA processing in Trypanosoma brucei

Albina Waithaka1, Christine Clayton2

  • 1Heidelberg University Centre for Molecular Biology (ZMBH), Im Neuenheimer Feld 282, D69120, Heidelberg, Germany.

BMC Research Notes
|December 17, 2022
PubMed
Abstract

Insights

Benzoxaboroles acoziborole and AN11736 inhibit mRNA processing in trypanosomes, similar to AN7973. CPSF73 protein interactions were unaffected by short-term AN7973 treatment.

Area of Science:

  • Molecular Biology
  • Parasitology
  • Drug Discovery

Background:

  • The CPSF73 endonuclease is a potential target for benzoxaborole anti-trypanosomal drugs.
  • Previous studies indicated AN7973 inhibits mRNA processing.
  • Acoziborole and AN11736 are drug candidates for human sleeping sickness and nagana in cattle, respectively.

Purpose of the Study:

  • To investigate if acoziborole and AN11736 inhibit mRNA processing in trypanosomes.
  • To analyze protein interactions with CPSF73 after AN7973 treatment using mass spectrometry.

Main Methods:

  • Assessed mRNA processing by measuring spliced mRNA levels and polycistronic transcripts.
  • Used affinity purification to isolate tagged CPSF73 from treated and untreated trypanosomes.
  • Employed mass spectrometry to identify differentially co-purified proteins.

Main Results:

  • AN11736 and acoziborole significantly inhibited mRNA processing.
  • Inhibition was evidenced by reduced spliced mRNAs and increased di- and tri-cistronic alpha-beta tubulin mRNAs.
  • Short-term (30 min) AN7973 treatment did not significantly alter CPSF73-associated proteins.

Conclusions:

  • Acoziborole and AN11736, like AN7973, target mRNA processing in trypanosomes.
  • These findings support the role of CPSF73 as a target for benzoxaborole drugs.
  • Further investigation is needed to understand the precise mechanism and short-term effects of AN7973 on CPSF73 interactions.
Keywords:
BenzoxaborolesCPSF73Tandem affinity purificationmRNA processing

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