Cording Amy, Gormally Michael, Bond Peter J, Carrington Mark, Balasubramanian Shankar, Miska Eric A, Thomas Beth
a The Gurdon Institute, University of Cambridge , Cambridge , UK.
b Department of Chemistry , University of Cambridge , Cambridge , UK.
RNA Biol. 2017 May 4;14(5):611-619. doi: 10.1080/15476286.2015.1137422. Epub 2016 Jan 20.
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.
非编码RNA是众多细胞过程的关键调节因子，并与人类疾病有关。这些生物学过程是我们对抗疾病中迄今尚未开发的资源。在这项工作中，我们鉴定了非编码RNA尿苷酸化途径的小分子抑制剂。TUTase酶家族对于调节人类癌症和病原体系统中的非编码RNA途径很重要。我们证明，可以通过传统的药物发现技术来利用这一新的药物靶点类别。利用布氏锥虫TUTase，即RET1，我们鉴定了TUTase抑制剂，并为将这一新的靶点类别用作非洲锥虫病这一服务不足疾病领域的治疗机会奠定了基础。从更广泛的意义上讲，这项工作证明了在人类疾病中用小分子靶向RNA转录后修饰的治疗潜力。
