化学合成mRNA短5'-UTR的选择提高翻译效率。

IF 1.5 4区 医学 Q4 CHEMISTRY, MEDICINAL
Sana Ohashi, Sumie Ishiguro, Tsukasa Fukunaga, Akinobu Matsumoto, Mina Hirata, Masahito Inagaki, Naoko Abe, Fumitaka Hashiya, Hiroshi Abe
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引用次数: 0

摘要

mRNA药物的出现最初是在2019年冠状病毒病(COVID-19)大流行期间作为疫苗实施的,引起了人们对多种治疗应用的兴趣,包括癌症疫苗和蛋白质替代疗法。我们小组最近建立了一种完全化学合成mRNA的方法。虽然这种方法有一些优点,但化学合成的mRNA的长度限制在大约150个核苷酸,并且需要优化设计非翻译区(utr)和编码序列。为了解决这一挑战,我们研究了非基于报告子的选择方法,包括核糖体分析和多体分析,这些方法通常用于长mRNA的UTR优化,是否可以适用于短mRNA,以识别高度翻译的UTR序列。利用这些方法,我们收集了与核糖体相互作用的mrna,并分析了它们的5'-UTR序列。我们成功地鉴定了一个9个核苷酸的5'-UTR,其翻译效率大约是广泛使用的阳性对照Kozak序列的两倍。这项工作突出了核糖体选择技术对短的、化学合成的mRNA的适应性,并为有效的序列设计提供了基础。这些发现推动了化学合成mRNA作为体外转录mRNA的可行替代品的发展,为创新的治疗应用铺平了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Selection of Short 5'-UTR of Chemically Synthesized mRNA to Improve Translation Efficiency.

The advent of mRNA medicine, initially implemented as a vaccine during the coronavirus disease 2019 (COVID-19) pandemic, has attracted interest in diverse therapeutic applications, including cancer vaccines and protein replacement therapies. Our group recently established a method for the complete chemical synthesis of mRNA. Although this approach has some advantages, chemically synthesized mRNA is limited to approximately 150 nucleotides in length and necessitates optimized designs for untranslated regions (UTRs) and coding sequences. To address this challenge, we investigated whether the non-reporter-based selection methods, including ribosome profiling and polysome profiling, which were often used for UTR optimization in long mRNA, could be adapted for short mRNA to identify highly translated UTR sequences. Using these methods, we collected mRNAs that interacted with ribosomes and analyzed their 5'-UTR sequences. We successfully identified a 9-nucleotide 5'-UTR that demonstrated approximately double the translation efficiency of the Kozak sequence, a widely used positive control. This work highlights the adaptability of ribosome-focused selection techniques for short, chemically synthesized mRNA and provides a foundation for effective sequence design. These findings advance the development of chemically synthesized mRNA as a viable alternative to in vitro-transcribed mRNA, paving the way for innovative therapeutic applications.

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来源期刊
CiteScore
3.20
自引率
5.90%
发文量
132
审稿时长
1.7 months
期刊介绍: The CPB covers various chemical topics in the pharmaceutical and health sciences fields dealing with biologically active compounds, natural products, and medicines, while BPB deals with a wide range of biological topics in the pharmaceutical and health sciences fields including scientific research from basic to clinical studies. For details of their respective scopes, please refer to the submission topic categories below. Topics: Organic chemistry In silico science Inorganic chemistry Pharmacognosy Health statistics Forensic science Biochemistry Pharmacology Pharmaceutical care and science Medicinal chemistry Analytical chemistry Physical pharmacy Natural product chemistry Toxicology Environmental science Molecular and cellular biology Biopharmacy and pharmacokinetics Pharmaceutical education Chemical biology Physical chemistry Pharmaceutical engineering Epidemiology Hygiene Regulatory science Immunology and microbiology Clinical pharmacy Miscellaneous.
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