Pilot-scale compound screening against RNA editing identifies trypanocidal agents.

Area of Science:

• Molecular Biology
• Parasitology
• Drug Discovery

Background:

• Mitochondrial mRNA in trypanosomatids undergoes RNA editing, a unique posttranscriptional modification.
• The editosome, a large protein complex, catalyzes RNA editing, essential for parasite survival.
• The editosome is a potential drug target due to its unique presence in trypanosomatids.

Purpose of the Study:

• To identify inhibitors of RNA editing using a high-throughput screen.
• To find novel tools for studying the editosome and RNA editing processes.
• To discover potential drug candidates against trypanosomatid infections.

Main Methods:

• Screening of the LOPAC1280 library of pharmacologically active compounds.
• High-throughput screening to identify inhibitors of deletion RNA editing.
• In vitro testing of identified compounds against Trypanosoma brucei.

Main Results:

• Aurintricarboxylic acid, mitoxantrone, PPNDS, and NF449 were identified as potent inhibitors of deletion RNA editing (IC50: 1-5 µM).
• None of the identified compounds specifically inhibited the catalytic steps of RNA editing.
• Mitoxantrone induced RNA-protein aggregates, while other compounds interfered with editosome-RNA interactions.
• NF449 demonstrated efficacy in killing Trypanosoma brucei in vitro.

Conclusions:

• New chemical tools have been identified for characterizing the editosome and its interactions.
• NF449 shows promise as both an RNA editing inhibitor and a potential therapeutic agent against trypanosomatid infections.
• Further research is needed to develop specific inhibitors targeting the catalytic steps of RNA editing.