Charge reduction and thermodynamic stabilization of substrate RNAs inhibit RNA editing

PloS One
W-Matthias LeederH U Göringer

Abstract

African trypanosomes cause a parasitic disease known as sleeping sickness. Mitochondrial transcript maturation in these organisms requires a RNA editing reaction that is characterized by the insertion and deletion of U-nucleotides into otherwise non-functional mRNAs. Editing represents an ideal target for a parasite-specific therapeutic intervention since the reaction cycle is absent in the infected host. In addition, editing relies on a macromolecular protein complex, the editosome, that only exists in the parasite. Therefore, all attempts to search for editing interfering compounds have been focused on molecules that bind to proteins of the editing machinery. However, in analogy to other RNA-driven biochemical pathways it should be possible to stall the reaction by targeting its substrate RNAs. Here we demonstrate inhibition of editing by specific aminoglycosides. The molecules bind into the major groove of the gRNA/pre-mRNA editing substrates thereby causing a stabilization of the RNA molecules through charge compensation and an increase in stacking. The data shed light on mechanistic details of the editing process and identify critical parameters for the development of new trypanocidal compounds.

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Citations

Aug 1, 2015·FEBS Letters·Anna CzerwoniecJanusz M Bujnicki
Jul 31, 2018·Nucleic Acids Research·Christin VoigtH Ulrich Göringer
Aug 7, 2020·Nucleic Acids Research·Cristian Del CampoH Ulrich Göringer

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Methods Mentioned

BETA
surface plasmon resonance
circular dichroism
NMR
X-ray

Software Mentioned

ERNA3D
APBS
PyMOL APBS
IGOR Pro
Autodock Vina
Autodock Tools
Origin
pdb2pqr

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