Kami Daisuke, Ishizaki Toshimasa, Taya Toshihiko, Katoh Akira, Kouji Hiroyuki, Gojo Satoshi
Department of Regenerative Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Department of Pharmacology, Faculty of Medicine, Oita University, Oita, Japan.
Cell Death Discov. 2022 Jun 7;8(1):278. doi: 10.1038/s41420-022-01076-4.
In cells, mRNA synthesis and decay are influenced by each other, and their balance is altered by either external or internal cues, resulting in changes in cell dynamics. We previously reported that it is important that an array of mRNAs that shape a phenotype are degraded before cellular transitions, such as cellular reprogramming and differentiation. In adipogenesis, the interaction between DDX6 and 4E-T had a definitive impact on the pathway in the processing body (PB). We screened a library of α-helix analogs with an alkaloid-like backbone to identify compounds that inhibit the binding between DDX6 and 4E-T proteins, which occurs between the α-helix of structured and internally disordered proteins. IAMC-00192 was identified as a lead compound. This compound directly inhibited the interaction between DDX6 and 4E-T. IAMC-00192 inhibited the temporal increase in PB formation that occurs during adipogenesis and epithelial-mesenchymal transition (EMT) and significantly suppressed these cellular transitions. In the EMT model, the half-life of preexisting mRNAs in PBs was extended twofold by the compound. The novel inhibitor of RNA decay not only represents a potentially useful tool to analyze in detail the pathological conditions affected by RNA decay and how it regulates the pathological state. The identification of this inhibitor may lead to the discovery of a first-in-class RNA decay inhibitor drug.
在细胞中，mRNA的合成与降解相互影响，其平衡会因外部或内部信号而改变，从而导致细胞动态变化。我们之前报道过，在细胞转变（如细胞重编程和分化）之前，一系列塑造表型的mRNA降解很重要。在脂肪生成过程中，DDX6与4E-T之间的相互作用对加工体（PB）中的信号通路有决定性影响。我们筛选了一个具有生物碱样骨架的α-螺旋类似物文库，以鉴定抑制DDX6与4E-T蛋白之间结合的化合物，这种结合发生在结构化和内在无序蛋白的α-螺旋之间。IAMC-00192被鉴定为先导化合物。该化合物直接抑制DDX6与4E-T之间的相互作用。IAMC-00192抑制脂肪生成和上皮-间质转化（EMT）过程中PB形成的时间性增加，并显著抑制这些细胞转变。在EMT模型中，该化合物使PB中现有mRNA的半衰期延长了两倍。这种新型RNA降解抑制剂不仅是详细分析受RNA降解影响的病理状况及其如何调节病理状态的潜在有用工具。这种抑制剂的鉴定可能会导致发现一类首创的RNA降解抑制剂药物。
