Selective inhibitors of trypanosomal uridylyl transferase RET1 establish druggability of RNA post-transcriptional modifications

RNA Biology
Amy CordingBeth Thomas

Abstract

Non-coding RNAs are crucial regulators for a vast array of cellular processes and have been implicated in human disease. These biological processes represent a hitherto untapped resource in our fight against disease. In this work we identify small molecule inhibitors of a non-coding RNA uridylylation pathway. The TUTase family of enzymes is important for modulating non-coding RNA pathways in both human cancer and pathogen systems. We demonstrate that this new class of drug target can be accessed with traditional drug discovery techniques. Using the Trypanosoma brucei TUTase, RET1, we identify TUTase inhibitors and lay the groundwork for the use of this new target class as a therapeutic opportunity for the under-served disease area of African Trypanosomiasis. In a broader sense this work demonstrates the therapeutic potential for targeting RNA post-transcriptional modifications with small molecules in human disease.

References

Jan 1, 1988·Fundamental & Clinical Pharmacology·H AllainJ Van den Driessche
Jul 1, 1997·Antimicrobial Agents and Chemotherapy·R W WinterM K Riscoe
Aug 19, 1997·Proceedings of the National Academy of Sciences of the United States of America·C HertelJ A Kemp
Apr 4, 2000·Toxicological Sciences : an Official Journal of the Society of Toxicology·S C LawsR L Cooper
Apr 2, 2003·Fundamental & Clinical Pharmacology·Bernard BouteilleMichel Dumas
Sep 5, 2003·Proceedings of the National Academy of Sciences of the United States of America·Ruslan AphasizhevLarry Simpson
Apr 3, 2004·The Journal of Biological Chemistry·Inna AphasizhevaLarry Simpson
Nov 6, 2004·Science·Binzhang Shen, Howard M Goodman
Dec 6, 2006·The New England Journal of Medicine·Steven E KahnUNKNOWN ADOPT Study Group
Feb 10, 2007·Nature Reviews. Drug Discovery·Philip J Hajduk, Jonathan Greer
Oct 8, 2009·Cancer Research·Matthias SchaeferFrank Lyko
Oct 22, 2009·Nucleic Acids Research·Martin AslettHaiming Wang
Jan 21, 2010·Molecular and Cellular Biology·Inna Aphasizheva, Ruslan Aphasizhev
May 25, 2011·Circulation·Johannes-Peter StaschOleg V Evgenov
Nov 19, 2011·Nature Reviews. Genetics·Manel Esteller
Nov 29, 2011·Cell·Elena PiskounovaRichard I Gregory
Dec 22, 2011·ACS Chemical Biology·Lirui Guan, Matthew D Disney
Jul 4, 2012·Nature Structural & Molecular Biology·Luke A YatesRobert J C Gilbert
Aug 14, 2012·Nucleic Acids Research·Bradley M LundeAnton Meinhart
May 7, 2013·Epigenetics : Official Journal of the DNA Methylation Society·Elsa SousaCarmen Jerónimo
Aug 31, 2013·Nature Reviews. Molecular Cell Biology·Chris J Norbury
Nov 1, 2013·Nature Reviews. Drug Discovery·Hui LingGeorge A Calin
Jun 27, 2015·RNA Biology·Shuibin Lin, Richard I Gregory
May 13, 2014·Journal of Chemical Theory and Computation·Teresa ParamoPeter J Bond

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Citations

Sep 20, 2016·Bioorganic & Medicinal Chemistry Letters·Ken AsadaZain Paroo
Apr 13, 2017·RNA Biology·Andrea Barta, Michael F Jantsch
Sep 18, 2020·Chemical Communications : Chem Comm·Jerrin Thomas George, Seergazhi G Srivatsan

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Methods Mentioned

BETA
chemical treatments
electrophoresis
phosphotransferase
PCR
Assay

Related Concepts

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African Trypanosomiasis

African trypanosomiasis, also known as sleeping sickness, is an insect-borne parasitic disease of humans and other animals. It is caused by protozoa of the species Trypanosoma brucei and almost invariably progresses to death unless treated. Discover the latest research on African trypanosomiasis here.

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