Department of Chemistry and Chemical Biology, University of New Mexico, 300 Terrace Street NE, Albuquerque, NM 87131, United States.
Department of Chemistry and Chemical Biology, University of New Mexico, 300 Terrace Street NE, Albuquerque, NM 87131, United States.
Bioorg Chem. 2018 Oct;80:492-497. doi: 10.1016/j.bioorg.2018.07.003. Epub 2018 Jul 2.
miRNAs are key cellular regulators and their dysregulation is associated with many human diseases. They are usually produced locally in a spatiotemporally controlled manner to target mRNAs and regulate gene expression. Thus, developing chemical tools for manipulating miRNA with spatiotemporal precise is critical for studying miRNA. Herein, we designed a strategy to control miRNA biogenesis with light controllable inhibitor targeting the pre-miRNA processing by Dicer. By conjugating two non-inhibiting units, a low affinity Dicer inhibitor and a pre-miRNA binder, through a photocleavable linker, the bifunctional molecule obtained could inhibit miRNA production. Taking advantage of the photocleavable property of the linker, the bifunctional inhibitor can be fragmented into separate non-inhibiting units and therefore be deactivated by light. We expect that this strategy could be applied to generate chemical biological tools that allow light-mediated spatiotemporal control of miRNA maturation and contribute to the study of miRNA function.
miRNAs 是关键的细胞调节剂，其失调与许多人类疾病有关。它们通常以时空控制的方式在局部产生，以靶向 mRNAs 并调节基因表达。因此，开发具有时空精确操纵 miRNA 的化学工具对于 miRNA 的研究至关重要。在此，我们设计了一种通过靶向 Dicer 的前体 miRNA 加工来用光控制抑制剂控制 miRNA 生成的策略。通过将两个非抑制性单元（低亲和力 Dicer 抑制剂和前体 miRNA 结合物）通过光可裂解的连接子连接起来，得到的双功能分子可以抑制 miRNA 的产生。利用连接子的光裂解性质，双功能抑制剂可以分解成单独的非抑制性单元，从而通过光失活。我们期望该策略可用于生成化学生物学工具，实现 miRNA 成熟的光介导时空控制，并有助于 miRNA 功能的研究。
