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Review
. 2011 Nov 13:2:36-46.
doi: 10.1016/j.ijpddr.2011.10.003. eCollection 2012 Dec.

Inhibitors of RNA editing as potential chemotherapeutics against trypanosomatid pathogens

Reza Salavati  1 , Houtan Moshiri  2 , Smriti Kala  3 , Hamed Shateri Najafabadi  4
Affiliations
Review

Inhibitors of RNA editing as potential chemotherapeutics against trypanosomatid pathogens

Reza Salavati et al. Int J Parasitol Drugs Drug Resist. .

Abstract

The related trypanosomatid pathogens, Trypanosoma brucei spp., Trypanosoma cruzi and Leishmania spp. cause devastating diseases in humans and animals and continue to pose a major challenge in drug development. Mitochondrial RNA editing, catalyzed by multi-protein complexes known as editosomes, has provided an opportunity for development of efficient and specific chemotherapeutic targets against trypanosomatid pathogens. This review will discuss both methods for discovery of RNA editing inhibitors, as well as inhibitors against the T. brucei editosome that were recently discovered through creative virtual and high throughput screening methods. In addition, the use of these inhibitors as agents that can block or perturb one or more steps of the RNA editing process will be discussed. These inhibitors can potentially be used to study the dynamic processing and assembly of the editosome proteins. A thorough understanding of the mechanisms and specificities of these new inhibitors is needed in order to contribute to both the functional studies of an essential gene expression mechanism and to the possibility of future drug development against the trypanosomatid pathogens.

Keywords: High-throughput screening; RNA editing inhibitor; Trypanosomatids; Virtual screening.

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Figures

None
Graphical abstract
Fig. 1
Fig. 1
Schematic presentation of RNA editing reactions. RNA editing entails maturation of the mitochondrial mRNAs by insertion (left panel) and deletion (right panel) of uridylates (Us) as specified by small guide RNAs (gRNAs). The specific proteins involved in each catalytic reaction are highlighted.
Fig. 2
Fig. 2
The schematic presentation of the three-step ligation mechanism of RNA editing ligase 1.
Fig. 3
Fig. 3
RNA editing assays that are developed for high-throughput screening – Left panel illustrates the RNA aptamer-based assay. In this assay, an aptamer that is labeled with ruthenium (red ball) is used, which upon successful addition of three Us changes conformation and, becomes activated, and thus binding to the streptavidin that coats the microtiter plate. Upon electrical stimulation, the ruthenium complex generates a measurable ECL signal. Right panel illustrates the FRET-based assay, in which the 16nt-long reporter RNA is labeled with a fluorescent reporter (FAM, red ball) and a fluorescent quencher (TAMRA, blue ball). In this assay, upon successful deletion of three Us from the catalytic core of HHR, the inactive HHR becomes active and cleaves the reporter RNA and generates a detectable fluorescent signal. (For interpretation of reference to colors in this figure legend, the reader is referred to the web version of this article.)
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