修饰的未锁定核酸（MUNA）减轻了小干扰rna的脱靶效应。

IF 13.1 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Nucleic Acids Research Pub Date : 2025-09-23 DOI:10.1093/nar/gkaf937

Shohei Mori,Dhrubajyoti Datta,Lydia Perkins,Michelle Jung,Lauren Blair Woods,Alex Eaton,June Qin,Tim Racie,MaryBeth Kim,Dale C Guenther,Adam Castoreno,Mark K Schlegel,Klaus Charisse,Martin Egli,Shigeo Matsuda,Muthiah Manoharan

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引用次数: 0

摘要

未锁定核酸（UNA）是一种核酸类似物，其无环核糖环缺乏C2‘和C3’原子之间的键。UNA的碱基配对特性已被研究，并被用作偶联支架，但围绕UNA的化学空间及其在介导RNA干扰的短干扰RNA （sirna）背景下的潜在应用尚未得到充分探索。在这项研究中，我们报道了甲基化和甲氧基化una的合成及其与sirna的结合。具有5'-(R)-甲基-UNA的siRNA和具有5'-(S)-甲基-UNA的siRNA在种子区具有相当的效力，但与UNA修饰的siRNA相比，脱靶效应较低。在小鼠中，具有修饰UNA的siRNA与具有相同序列和化学性质的缺乏UNA的siRNA具有相当的效力。建模研究表明，UNA和修饰的UNA的柔韧性有助于在第7位加入反义链时发生扭结。这些发现突出了改进的UNA在推进通过RNA干扰途径起作用的治疗方面的潜力。

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Modified unlocked nucleic acid (MUNA) mitigates off-target effects of small interfering RNAs.

Unlocked nucleic acid (UNA) is a nucleic acid analog that has an acyclic ribose ring lacking the bond between C2' and C3' atoms. The base-pairing properties of UNA have been studied, and it has been used as a scaffold for conjugation, but the chemical space around UNA and its potential applications in the context of short interfering RNAs (siRNAs), which mediate RNA interference, have not been thoroughly explored. In this study, we report syntheses of methylated and methoxylated UNAs and their incorporation into siRNAs. siRNAs with 5'-(R)-methyl-UNA and with 5'-(S)-methyl-UNA in the seed region had comparable potencies but reduced off-target effects compared to siRNA modified with UNA. In mice, siRNAs with modified UNAs were of comparable potency to an siRNA of the same sequence and chemistry lacking UNA. Modeling studies indicated that the flexibilities of UNA and the modified UNAs facilitate kinking of the antisense strand when incorporated at position 7. These findings highlight the potential of modified UNA for advancing therapeutics that act through the RNA interference pathway.

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来源期刊

Nucleic Acids Research 生物-生化与分子生物学

CiteScore

27.10

自引率

4.70%

发文量

1057

审稿时长

2 months

期刊介绍： Nucleic Acids Research (NAR) is a scientific journal that publishes research on various aspects of nucleic acids and proteins involved in nucleic acid metabolism and interactions. It covers areas such as chemistry and synthetic biology, computational biology, gene regulation, chromatin and epigenetics, genome integrity, repair and replication, genomics, molecular biology, nucleic acid enzymes, RNA, and structural biology. The journal also includes a Survey and Summary section for brief reviews. Additionally, each year, the first issue is dedicated to biological databases, and an issue in July focuses on web-based software resources for the biological community. Nucleic Acids Research is indexed by several services including Abstracts on Hygiene and Communicable Diseases, Animal Breeding Abstracts, Agricultural Engineering Abstracts, Agbiotech News and Information, BIOSIS Previews, CAB Abstracts, and EMBASE.