Department of Regulatory Bioorganic Chemistry, The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan.
Department of Life and Environmental Sciences, Faculty of Engineering, Chiba Institute of Technology, Chiba 275-0016, Japan.
Bioorg Med Chem. 2019 May 15;27(10):2140-2148. doi: 10.1016/j.bmc.2019.03.031. Epub 2019 Mar 18.
Small-molecule modulators, along with antisense oligonucleotide, would be powerful tools and potential drug candidates for modulating miRNA-related gene expressions. The mechanism of the inhibitory effect of the C-bulge binding small molecule BzDANP for the Dicer processing reaction of pre-miR-136 was discussed on the data obtained by SPR, NMR, and kinetic analysis for Dicer processing. SPR and NMR analysis showed the preference of BzDANP binding to the C-bulge. Michaelis-Menten analysis suggested the formation of a ternary complex pre-miR-136-BzDANP-Dicer during the Dicer-cleavage reaction of pre-miR-136 in the presence of BzDANP. The inhibitory effect of BzDANP is likely attributed to the slower reaction from the ternary complex than that from the binary pre-miR-136-Dicer complex.
小分子调节剂与反义寡核苷酸一起，将成为调节 miRNA 相关基因表达的有力工具和潜在药物候选物。通过 SPR、NMR 和动力学分析 Dicer 加工反应获得的数据，讨论了 C-突环结合小分子 BzDANP 对 pre-miR-136 的 Dicer 加工反应的抑制作用机制。SPR 和 NMR 分析表明 BzDANP 优先结合 C-突环。米氏分析表明，在 BzDANP 存在下，pre-miR-136 的 Dicer 切割反应过程中形成了 pre-miR-136-BzDANP-Dicer 三元复合物。BzDANP 的抑制作用可能归因于三元复合物的反应速度比二元 pre-miR-136-Dicer 复合物的反应速度慢。
