New and versatile chemical approaches for the synthesis of mRNA and tRNA

用于合成 mRNA 和 tRNA 的新型多功能化学方法

• 批准号: BB/R008655/1
• 负责人: Tom Brown
• 金额: $ 92.19万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR008655%2F1
• 关键词: New; versatile; chemical; approaches; synthesis

The central dogma of molecular biology states that "DNA makes RNA makes proteins." We are interested in the possibility of intercepting the second step "RNA makes proteins." Two different RNA molecules, messenger RNA (mRNA) and transfer RNA (tRNA) are required in this step; they combine to convert the four letter code of DNA into the sequence of a protein. In principle this process could be manipulated by chemists who can assemble RNA by automated solid-phase methods. This would make it possible to produce chemically modified RNA and in turn modified proteins with new and improved properties by including unnatural building blocks (amino-acids). However, making the required long modified RNA strands to achieve this is beyond the scope of current chemical methods which are based on solid-phase synthesis. Therefore we will develop a new methodology, solid-phase synthesis of RNA combined with chemical ligation, to join together several chemically synthesised RNA strands in a chain to make mRNA molecules that are large enough to be used as therapeutic molecules and which can also be used to make useful proteins. Our synthetic mRNA (chemRNA) will have many advantages over biologically produced RNA. In particular it can be made on a very large scale, and it is possible to introduce many exotic chemical modifications that are not available to biological systems to enhance its stability and improve its ability to target particular organs in the body. This is an important objective because biochemically-derived, mRNA is starting to show promise in immunotherapy, infectious disease control and cancer therapy. Indeed, some mRNAs have even entered clinical trials. However, their development is limited by the difficulty in modifying them to make them stable in the human body. ChemRNA could also be used in combination with chem-tRNA to make proteins that cannot be made by current biochemical or biological methods. Chemical evolution in a test tube could then be used to produce new proteins with enhanced properties for use in many fields including biotechnology and synthetic biology.

分子生物学的中心法则说：“DNA制造RNA制造蛋白质。“我们对拦截第二步的可能性感兴趣”RNA制造蛋白质。“这一步需要两种不同的RNA分子，信使RNA（mRNA）和转移RNA（tRNA）;它们联合收割机将DNA的四个字母密码转化为蛋白质的序列。原则上，这一过程可以由能够通过自动化固相方法组装RNA的化学家来操纵。这将使得有可能产生化学修饰的RNA，进而通过包括非天然构建块（氨基酸）而具有新的和改进的特性的修饰蛋白质。然而，制备所需的长修饰RNA链以实现这一点超出了基于固相合成的当前化学方法的范围。因此，我们将开发一种新的方法，结合化学连接的RNA固相合成，将几条化学合成的RNA链连接在一起，以制造足够大的mRNA分子，以用作治疗分子，也可以用于制造有用的蛋白质。我们的合成mRNA（chemRNA）将比生物产生的RNA具有许多优势。特别是它可以在非常大的规模上进行，并且可以引入许多生物系统无法获得的外来化学修饰，以增强其稳定性并提高其靶向体内特定器官的能力。这是一个重要的目标，因为生物化学衍生的mRNA开始在免疫治疗，传染病控制和癌症治疗中显示出希望。事实上，一些mRNA甚至已经进入临床试验。然而，它们的发展受到难以对其进行修饰以使其在人体内稳定的限制。ChemRNA还可以与chem-tRNA结合使用，以制造目前生物化学或生物学方法无法制造的蛋白质。然后，试管中的化学进化可以用来生产具有增强特性的新蛋白质，用于包括生物技术和合成生物学在内的许多领域。

项目成果

Searching for the ideal triazole: Investigating the 1,5-triazole as a charge neutral DNA backbone mimic

• DOI: 10.1016/j.tet.2019.130914
• 发表时间: 2020-02-14
• 期刊: TETRAHEDRON
• 影响因子: 2.1
• 作者: Baker, Ysobel R.;Traore, Diallo;Brown, Tom
• 通讯作者: Brown, Tom

Expanding the chemical functionality of DNA nanomaterials generated by rolling circle amplification.

• DOI: 10.1093/nar/gkab720
• 发表时间: 2021-09-20
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Baker YR;Yuan L;Chen J;Belle R;Carlisle R;El-Sagheer AH;Brown T
• 通讯作者: Brown T

A New 1,5-Disubstituted Triazole DNA Backbone Mimic with Enhanced Polymerase Compatibility.

• DOI: 10.1021/jacs.1c08057
• 发表时间: 2021-10-06
• 期刊: Journal of the American Chemical Society
• 影响因子: 15
• 作者: Epple S;Modi A;Baker YR;Wȩgrzyn E;Traoré D;Wanat P;Tyburn AES;Shivalingam A;Taemaitree L;El-Sagheer AH;Brown T
• 通讯作者: Brown T

Covalently attached intercalators restore duplex stability and splice-switching activity to triazole-modified oligonucleotides.

• DOI: 10.1039/d2cb00100d
• 发表时间: 2022-06-08
• 期刊: RSC CHEMICAL BIOLOGY
• 影响因子: 4.1
• 作者: Dysko, Anna;Baker, Ysobel R.;McClorey, Graham;Wood, Matthew J. A.;Fenner, Sabine;Williams, Glynn;El-Sagheer, Afaf;Brown, Tom
• 通讯作者: Brown, Tom

Artificial nucleic acid backbones and their applications in therapeutics, synthetic biology and biotechnology.

• DOI: 10.1042/etls20210169
• 发表时间: 2021-11-12
• 期刊: Emerging topics in life sciences
• 影响因子: 3.8
• 作者: Epple S;El-Sagheer AH;Brown T
• 通讯作者: Brown T