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Control of RNA with quinone methide reversible acylating reagents
Organic & Biomolecular Chemistry ( IF 2.9 ) Pub Date : 2021-09-13 , DOI: 10.1039/d1ob01713f
Hyun Shin Park 1 , Biswarup Jash 1 , Lu Xiao 1 , Yong Woong Jun 1 , Eric T Kool 1
Affiliation  

Caging RNA by polyacylation (cloaking) has been developed recently as a simple and rapid method to control the function of RNAs. Previous approaches for chemical reversal of acylation (uncloaking) made use of azide reduction followed by amine cyclization, requiring ∼2–4 h for the completion of cyclization. In new studies aimed at improving reversal rates and yields, we have designed novel acylating reagents that utilize quinone methide (QM) elimination for reversal. The QM de-acylation reactions were tested with two bioorthogonally cleavable motifs, azide and vinyl ether, and their acylation and reversal efficiencies were assessed with NMR and mass spectrometry on model small-molecule substrates as well as on RNAs. Successful reversal both with phosphines and strained alkenes was documented. Among the compounds tested, the azido-QM compound A-3 displayed excellent de-acylation efficiency, with t1/2 for de-acylation of less than an hour using a phosphine trigger. To test its function in RNA caging, A-3 was successfully applied to control EGFP mRNA translation in vitro and in HeLa cells. We expect that this molecular caging strategy can serve as a valuable tool for biological investigation and control of RNAs both in vitro and in cells.

中文翻译:


用醌甲基化物可逆酰化试剂控制 RNA



最近开发了通过多酰化(隐藏)来封闭 RNA,作为控制 RNA 功能的简单而快速的方法。以前的化学逆转酰化(揭开)的方法利用叠氮化物还原,然后进行胺环化,需要〜2-4小时才能完成环化。在旨在提高逆转率和产量的新研究中,我们设计了利用醌甲基化物 (QM) 消除来逆转的新型酰化试剂。使用两种生物正交可裂解基序(叠氮化物和乙烯基醚)测试了 QM 去酰化反应,并使用 NMR 和质谱法对模型小分子底物以及 RNA 评估了它们的酰化和逆转效率。记录了膦和应变烯烃的成功逆转。在测试的化合物中,叠氮基-QM 化合物A-3显示出优异的脱酰化效率,使用膦触发剂的脱酰化时间为t 1/2 ,时间少于一小时。为了测试其在 RNA 笼蔽中的功能, A-3成功应用于体外和 HeLa 细胞中控制 EGFP mRNA 翻译。我们期望这种分子笼策略可以作为体外和细胞内 RNA 的生物学研究和控制的有价值的工具。
更新日期:2021-09-16
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