具有稳定结构的工程 mRNA 可最大限度地减少双链 RNA 的形成,提高蛋白质的表达。

IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Molecular Biology Pub Date : 2024-10-19 DOI:10.1016/j.jmb.2024.168822
Qianshan Qin , Huayuan Yan , Weixiang Gao , Ruyin Cao , Guopeng Liu , Xiaojing Zhang , Niangang Wang , Wenjie Zuo , Lei Yuan , Peng Gao , Qi Liu
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引用次数: 0

摘要

合成信息 RNA(mRNA)的治疗用途已在 COVID-19 疫苗中得到验证,并在开发传染病和肿瘤疫苗方面显示出巨大的潜力。然而,体外转录(IVT)过程中产生的双链 RNA(dsRNA)副产物会降低基于 mRNA 的疗法的疗效,并引发先天性免疫反应。消除dsRNA副产物的现有方法通常既繁琐又耗费人力。在这项研究中,我们发现松散的 mRNA 二级结构和序列中更多未配对的 U 碱基通常会导致在 IVT 过程中形成更多的 dsRNA 副产物。我们根据序列特征进一步开发了dsRNA副产物形成的预测模型,以指导 mRNA 序列的优化,从而帮助减少不必要的免疫反应,提高 mRNA 产物的蛋白质表达。总之,我们的研究为开发有效的 mRNA 疗法提供了新的线索和方法,从而最大限度地减少 dsRNA 副产物,提高蛋白质表达。
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Engineered mRNAs With Stable Structures Minimize Double-stranded RNA Formation and Increase Protein Expression
The therapeutic use of synthetic message RNA (mRNA) has been validated in COVID-19 vaccines and shows enormous potential in developing infectious and oncological vaccines. However, double-stranded RNA (dsRNA) byproducts generated during the in vitro transcription (IVT) process can diminish the efficacy of mRNA-based therapeutics and provoke innate immune responses. Existing methods to eliminate dsRNA byproducts are often cumbersome and labor-intensive. In this study, we revealed that a loose mRNA secondary structure and more unpaired U bases in the sequence generally lead to the formation of more dsRNA byproducts during the IVT process. We further developed a predictive model for dsRNA byproducts formation based on sequence characteristics to guide the optimization of mRNA sequences, helping to minimize unwanted immune response and improve the protein expression of mRNA products. Collectively, our study provides novel clues and methodologies for developing effective mRNA therapeutics with minimized dsRNA byproducts and increased protein expression.
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来源期刊
Journal of Molecular Biology
Journal of Molecular Biology 生物-生化与分子生物学
CiteScore
11.30
自引率
1.80%
发文量
412
审稿时长
28 days
期刊介绍: Journal of Molecular Biology (JMB) provides high quality, comprehensive and broad coverage in all areas of molecular biology. The journal publishes original scientific research papers that provide mechanistic and functional insights and report a significant advance to the field. The journal encourages the submission of multidisciplinary studies that use complementary experimental and computational approaches to address challenging biological questions. Research areas include but are not limited to: Biomolecular interactions, signaling networks, systems biology; Cell cycle, cell growth, cell differentiation; Cell death, autophagy; Cell signaling and regulation; Chemical biology; Computational biology, in combination with experimental studies; DNA replication, repair, and recombination; Development, regenerative biology, mechanistic and functional studies of stem cells; Epigenetics, chromatin structure and function; Gene expression; Membrane processes, cell surface proteins and cell-cell interactions; Methodological advances, both experimental and theoretical, including databases; Microbiology, virology, and interactions with the host or environment; Microbiota mechanistic and functional studies; Nuclear organization; Post-translational modifications, proteomics; Processing and function of biologically important macromolecules and complexes; Molecular basis of disease; RNA processing, structure and functions of non-coding RNAs, transcription; Sorting, spatiotemporal organization, trafficking; Structural biology; Synthetic biology; Translation, protein folding, chaperones, protein degradation and quality control.
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