Association of a peptoid ligand with the apical loop of pri-miR-21 inhibits cleavage by Drosha.
Association of a peptoid ligand with the apical loop of pri-miR-21 inhibits cleavage by Drosha.
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DOI：
10.1261/rna.042911.113
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发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Luebke KJ
中科院分区：
文献类型：
--
作者：
Diaz JP;Chirayil R;Chirayil S;Tom M;Head KJ;Luebke KJ
近年来，越来越多的证据表明miRNA生物合成受到广泛的转录后调控。这有时通过RNA结合蛋白与前体miRNA的末端环结合来实现，并影响Drosha和/或Dicer加工。在这项研究中，作者合成了一个小的类肽库，并分析了它们与pri-miR-21的茎和顶端环区域相关的RNA模型结构的结合。他们鉴定了一种类肽配体，其通过与其顶端环结构结合来抑制miR-21初级转录物的加工。这代表了通过结合pri-miRNA的末端环来抑制微处理器介导的加工的小分子的第一个例子。我们已经发现了一种小分子，它特异性地抑制Drosha和DGCR 8的微处理器复合物对致癌miRNA的前体miR-21的切割。我们从14，024个N-取代的寡甘氨酸（类肽）的微阵列形式的筛选中确定了这种前体的顶端环的新型配体。获得了具有特异性亲和力的八种不同化合物，其中三种对低微摩尔范围内的靶向环具有亲和力，并且对密切相关的发夹具有大于15倍的辨别力。这些化合物之一在另一种miRNA初级转录物pri-miR-16的切割几乎不受影响的浓度下完全抑制miR-21初级转录物的微处理器切割。置于pri-miR-16的背景下的pri-miR-21的顶端环足以抑制类肽对微处理器的切割。该化合物还抑制含有pri-miR-16顶端环的pri-miR-21的切割，表明pri-miR-21内存在额外的缔合位点。报道的类肽是第一个通过与pri-miRNA的顶端环结合来抑制微处理器切割的小分子的例子。
In recent years, there has been increasing evidence of extensive post-transcriptional regulation of miRNA biogenesis. This is sometimes accomplished by binding of RNA-binding proteins to the terminal loop of precursor miRNAs and affects Drosha and/or Dicer processing. In this study, the authors synthesized a small library of peptoids and analyzed their binding to an RNA model structure related to the stem and apical loop region of pri-miR-21. They identified a peptoid ligand that suppresses processing of a miR-21 primary transcript by association with its apical loop structure. This represents the first example of a small molecule that inhibits microprocessor-mediated processing by binding to the terminal loop of a pri-miRNA. We have found a small molecule that specifically inhibits cleavage of a precursor to the oncogenic miRNA, miR-21, by the microprocessor complex of Drosha and DGCR8. We identified novel ligands for the apical loop of this precursor from a screen of 14,024 N-substituted oligoglycines (peptoids) in a microarray format. Eight distinct compounds with specific affinity were obtained, three having affinities for the targeted loop in the low micromolar range and greater than 15-fold discrimination against a closely related hairpin. One of these compounds completely inhibits microprocessor cleavage of a miR-21 primary transcript at concentrations at which cleavage of another miRNA primary transcript, pri-miR-16, is little affected. The apical loop of pri-miR-21, placed in the context of pri-miR-16, is sufficient for inhibition of microprocessor cleavage by the peptoid. This compound also inhibits cleavage of pri-miR-21 containing the pri-miR-16 apical loop, suggesting an additional site of association within pri-miR-21. The reported peptoid is the first example of a small molecule that inhibits microprocessor cleavage by binding to the apical loop of a pri-miRNA.
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DOI：
10.1146/annurev.pathol.4.110807.092222
发表时间：
2009
期刊：
Annual review of pathology
影响因子：
--
作者：
Lee YS;Dutta A
通讯作者：
Dutta A
影响因子：
64.5
作者：
Han, Jinju;Lee, Yoontae;Kim, V. Narry
通讯作者：
Kim, V. Narry
影响因子：
9.2
作者：
Landthaler, M;Yalcin, A;Tuschl, T
通讯作者：
Tuschl, T
影响因子：
1.8
作者：
Chirayil, Sara;Luebke, Kevin J.
通讯作者：
Luebke, Kevin J.
影响因子：
7.5
作者：
Chekulaeva, Marina;Filipowicz, Witold
通讯作者：
Filipowicz, Witold