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N2修饰的帽子类似物作为翻译抑制剂和治疗性mRNA制备底物。

N2 modified cap analogues as translation inhibitors and substrates for preparation of therapeutic mRNA.

发表日期:2023 Sep 01
作者: Karol Kurpiejewski, Marzena Jankowska-Anyszka, Renata Grzela
来源: Stem Cell Research & Therapy

摘要:

近年来,许多科学家开始关注mRNA分子作为新型药物的出现。其作为疫苗技术的快速发展和成功可不能被低估。mRNA提供了新的机会,并且可以以低成本快速制备有效的药物。这些广泛的可能性源于多种因素,但位于mRNA的5'端的小帽子结构是其中的一个因素。帽子结构保护mRNA,并确保其有效地被招募到生物合成机制中。此外,它使得各种影响整个mRNA活性的修饰很容易引入。在已报道的许多不同的帽子类似物中,对鸟苷的N2位置进行修饰已经被系统地开发。以核苷酸单磷酸或二核苷酸的形式存在的N2修饰的帽子显示出良好的生物学特性,以及在无细胞RRL体系中抑制翻译过程的高能力。修改的N2二核苷酸能够高效地被嵌入到mRNA转录本的结构中,在特定情况下以正确的方向,使其成为ARCA类类似物的有趣替代品。此外,含有在外环胺基团内修饰的帽子结构的mRNA转录本表现出非常高的翻译活性。因此,N2位置修饰的类似物可能有望成为治疗癌症各种表现形式的治疗药物,以及RNA工程中理想的工具。 © 2023. 作者。
In recent years many scientists have begun to focus on the mRNA molecule's emeregence as a new type of drug. Its fast-moving and successful career as a vaccine technology cannot be underestimated. mRNA provides new opportunities and allows for the rapid preparation of effective drugs at low cost. These extensive possibilities stem from a number of factors, but the small cap structure located at the 5' end of the mRNA is one contributing factor. Cap protects mRNA and ensures efficient recruitment to the biosynthesis machinery. Furthermore, it allows for the easy introduction of various modifications that influence the activity of the entire mRNA. Among the many different cap analogues that have been reported, those modified at the N2 position of guanosine have been systematically developed. N2-modified caps in the form of nucleoside monophosphates or dinucleotides show favorable biological properties, as well as a high capacity to inhibit the translation process in the cell-free RRL system. Modified N2 dinucleotides are efficiently incorporated into the structure of the mRNA transcript, and in specific circumstances with the correct orientation, making them an interesting alternative for ARCA-type analogues. Moreover, mRNA transcripts containing cap structures modified within the exocyclic amino group show very high translational activity. Therefore, analogues modified at the N2 position may have future applications as therapeutics against various manifestations of cancer and as desirable tools in RNA engineering.© 2023. The Author(s).