Abstract
ABSTRACTNon-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.
Highlights
RNA plays a vital role in multiple cellular processes, and is involved in many disease states, yet drugs that directly target RNA are rare.[1,2] Interest in how this rich source of potential drug targets can be can be tapped continues to grow
Using the Trypanosoma brucei terminal uridylyl transferase (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
Homology between RET1 in T. brucei and Leishmania infantum is high in the domains surrounding the active site (Fig. S8) and it is plausible that the RET1 inhibition that we report here may contribute to their mode of action
Summary
RNA plays a vital role in multiple cellular processes, and is involved in many disease states, yet drugs that directly target RNA are rare.[1,2] Interest in how this rich source of potential drug targets can be can be tapped continues to grow. Active site and make them attractive targets for small molecule therapy.[8] There are both endogenous and exogenous examples of RNA uridylyl transferases relevant in human disease, for example, human TUT4, which controls the stability of the Let-7 family of miRNAs and has been linked to some forms of cancer.[9,10] Complementary to this work, the first TUT4 inhibitors have been recently reported in this journal.[11] The trypanosome TUTase, RET1, has multiple essential roles for the parasite’s survival in a host, including the uridylylation of long non-coding guide RNAs (gRNAs).[12] Infection of human hosts by trypanosomes is responsible for several illnesses including Human African Trypanosomiasis (sleeping sickness) and Chagas disease which cause devastation in the developing world.
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