Towards SINEUP-based therapeutics: Design of an in vitro synthesized SINEUP RNA.

IF 1.9 4区环境科学与生态学 Q3 ENVIRONMENTAL STUDIES Disaster Prevention and Management Pub Date : 2022-02-02 eCollection Date: 2022-03-08 DOI:10.1016/j.omtn.2022.01.021

Paola Valentini, Bianca Pierattini, Elsa Zacco, Damiano Mangoni, Stefano Espinoza, Natalie A Webster, Byron Andrews, Piero Carninci, Gian Gaetano Tartaglia, Luca Pandolfini, Stefano Gustincich

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Abstract

SINEUPs are a novel class of natural and synthetic non-coding antisense RNA molecules able to increase the translation of a target mRNA. They present a modular organization comprising an unstructured antisense target-specific domain, which sets the specificity of each individual SINEUP, and a structured effector domain, which is responsible for the translation enhancement. In order to design a fully functional in vitro transcribed SINEUP for therapeutics applications, SINEUP RNAs were synthesized in vitro with a variety of chemical modifications and screened for their activity on endogenous target mRNA upon transfection. Three combinations of modified ribonucleotides-2'O methyl-ATP (Am), N6 methyl-ATP (m6A), and pseudo-UTP (ψ)-conferred SINEUP activity to naked RNA. The best combination tested in this study was fully modified with m6A and ψ. Aside from functionality, this combination conferred improved stability upon transfection and higher thermal stability. Common structural determinants of activity were identified by circular dichroisms, defining a core functional structure that is achieved with different combinations of modifications.

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迈向基于 SINEUP 的疗法：设计体外合成的 SINEUP RNA。

SINEUPs 是一类新型的天然和合成非编码反义 RNA 分子，能够增强目标 mRNA 的翻译。它们具有模块化的组织结构，包括一个非结构化的反义目标特异性结构域和一个结构化的效应结构域，前者设定了每个 SINEUP 的特异性，后者则负责翻译增强。为了设计出用于治疗的全功能体外转录 SINEUP，我们在体外合成了经过多种化学修饰的 SINEUP RNA，并筛选了它们在转染后对内源性靶 mRNA 的活性。三种修饰核糖核苷酸组合--2'O 甲基-ATP（Am）、N6 甲基-ATP（m6A）和假-UTP（ψ）--赋予裸 RNA SINEUP 活性。本研究中测试的最佳组合是经 m6A 和 ψ 完全修饰的组合。除功能性外，这种组合还提高了转染时的稳定性和热稳定性。通过圆二色性分析确定了活性的共同结构决定因素，定义了不同修饰组合可实现的核心功能结构。

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来源期刊

Disaster Prevention and Management Multiple-

CiteScore

4.40

自引率

10.50%

发文量

期刊介绍： Disaster Prevention and Management, An International Journal, sets out to advance the available knowledge in the fields of disaster prevention and management and to act as an integrative agent for extant methodologies and activities relating to disaster emergency and crisis management. Publishing high quality, refereed papers, the journal supports the exchange of ideas, experience and practice between academics, practitioners and policy-makers.