1. Pilot-Scale Screening of Clinically Approved Drugs to Identify Uridine Insertion/Deletion RNA Editing Inhibitors in Trypanosoma brucei .
- Author
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Rostamighadi M, Kamelshahroudi A, Pitsitikas V, Jacobson KA, and Salavati R
- Subjects
- Trypanocidal Agents pharmacology, Trypanocidal Agents chemistry, Humans, Drug Evaluation, Preclinical, Protozoan Proteins genetics, Protozoan Proteins antagonists & inhibitors, Protozoan Proteins metabolism, Molecular Docking Simulation, Drug Repositioning, Catechin pharmacology, Catechin analogs & derivatives, Catechin chemistry, Trypanosoma brucei brucei drug effects, Trypanosoma brucei brucei genetics, RNA Editing, Uridine analogs & derivatives, Uridine pharmacology, Uridine chemistry
- Abstract
RNA editing pathway is a validated target in kinetoplastid parasites ( Trypanosoma brucei , Trypanosoma cruzi , and Leishmania spp.) that cause severe diseases in humans and livestock. An essential large protein complex, the editosome, mediates uridine insertion and deletion in RNA editing through a stepwise process. This study details the discovery of editosome inhibitors by screening a library of widely used human drugs using our previously developed in vitro biochemical Ribozyme Insertion Deletion Editing (RIDE) assay. Subsequent studies on the mode of action of the identified hits and hit expansion efforts unveiled compounds that interfere with RNA-editosome interactions and novel ligase inhibitors with IC
50 values in the low micromolar range. Docking studies on the ligase demonstrated similar binding characteristics for ATP and our novel epigallocatechin gallate inhibitor. The inhibitors demonstrated potent trypanocidal activity and are promising candidates for drug repurposing due to their lack of cytotoxic effects. Further studies are necessary to validate these targets using more definitive gene-editing techniques and to enhance the safety profile.- Published
- 2024
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