美国斯坦福大学教授Kool, Eric T.团队报道了可逆的2′-OH酰化增强了RNA的稳定性。相关研究成果于2023年6月26日发表于国际顶尖学术期刊《自然—化学》。

核糖中2′-位的羟基使核糖核酸易于水解。因此，RNA在储存、运输和生物应用中的稳定化仍然是一个严峻的挑战，尤其是对于无法通过化学合成获得的较大RNA。

该文中，研究人员提出了可逆的2′-OH酰化作为保存任何长度或来源的RNA的一般策略。通过容易获得的酰基咪唑试剂进行的2′-羟基的高产聚酰化（“漂浮”）有效地保护RNA免受热降解和酶降解。随后用水溶性亲核试剂处理可以定量地去除酰化加合物（“包埋”），并恢复非常广泛的RNA功能，包括逆转录、翻译和基因编辑。此外，研究人员发现某些α-二甲基氨基和α-烷氧基-酰基加合物在人类细胞中被自发去除，恢复信使RNA翻译并延长其功能半衰期。这些发现支持了可逆2′-酰化作为一种简单通用的分子溶液提高RNA稳定性的潜力，并为稳定RNA提供了机制见解，无论其长度或来源如何。

附：英文原文

Title: Reversible 2′-OH acylation enhances RNA stability

Author: Fang, Linglan, Xiao, Lu, Jun, Yong Woong, Onishi, Yoshiyuki, Kool, Eric T.

Issue&Volume: 2023-06-26

Abstract: The presence of a hydroxyl group at the 2′-position in its ribose makes RNA susceptible to hydrolysis. Stabilization of RNAs for storage, transport and biological application thus remains a serious challenge, particularly for larger RNAs that are not accessible by chemical synthesis. Here we present reversible 2′-OH acylation as a general strategy to preserve RNA of any length or origin. High-yield polyacylation of 2′-hydroxyls (‘cloaking’) by readily accessible acylimidazole reagents effectively shields RNAs from both thermal and enzymatic degradation. Subsequent treatment with water-soluble nucleophilic reagents removes acylation adducts quantitatively (‘uncloaking’) and recovers a remarkably broad range of RNA functions, including reverse transcription, translation and gene editing. Furthermore, we show that certain α-dimethylamino- and α-alkoxy- acyl adducts are spontaneously removed in human cells, restoring messenger RNA translation with extended functional half-lives. These findings support the potential of reversible 2′-acylation as a simple and general molecular solution for enhancing RNA stability and provide mechanistic insights for stabilizing RNA regardless of length or origin.

DOI: 10.1038/s41557-023-01246-6

Source: https://www.nature.com/articles/s41557-023-01246-6