Scalable Production of Precisely Engineered Proteins Using an Expanded Genetic Code

使用扩展的遗传密码大规模生产精确工程蛋白质

• 批准号: BB/Y00812X/1
• 负责人: Anthony Green
• 金额: $ 219.26万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY00812X%2F1
• 关键词: Scalable; Production; Precisely; Engineered; Proteins

Proteins are biopolymers that perform a vast array of functions in nature, including speeding up the biochemical reactions needed for life, transporting molecules across membranes, providing structural support and controlling signalling processes. Beyond their natural functions, proteins are also used widely across chemistry, biotechnology and medicine - for example as therapeutics such as insulin or as biocatalysts used in laundry detergents or to break down plastics. Despite their remarkable structural and functional diversity, the vast majority of proteins are made from only 20 standard building blocks, the canonical amino acids. These amino acids only contain a narrow set of functional motifs, which ultimately restricts our ability to develop proteins with new and improved functions. To address this fundamental limitation, a powerful protein engineering technique called genetic code expansion (GCE) has been developed to allow proteins to be produced from >20 amino acid building blocks. Using this technique, hundreds of non-canonical amino acids (ncAAs) with new functional side chains can now be selectively introduced into proteins, leading to the development of new generations of biocatalysts, advanced materials and new biotherapeutics. However, despite great progress and its enormous commercial potential, the translation of GCE from academic labs into commercial protein products has been hindered by existing limitations of the technology. Current barriers to translation include the low yields of ncAA-containing proteins and the requirement for large excesses of ncAAs, which ultimately result in prohibitively high production costs. In this proposal we will develop a fully integrated engineering biology platform to translate GCE into commercial applications. Bringing together multidisciplinary researchers from across academia and industry, we will develop engineered strains capable of biosynthesizing new functional ncAAs and efficiently introduce them into proteins to deliver precisely functionalized proteins at substantially lower costs than existing platforms. To exemplify our technology, we will work in collaboration with our industrial partners AstraZeneca, GSK and Prozomix, to apply our engineered strains to the large-scale production of next generation biocatalysts and protein therapeutics. Moving forward, the versatile GCE platform and engineering biology tools developed within this proposal will enable the scalable production of diverse functionalized proteins in response to emerging societal needs.

蛋白质是在自然界中执行大量功能的生物聚合物，包括加快生命所需的生化反应，在跨膜跨膜上运输分子，提供结构支持和控制信号传导过程。除了它们的自然功能外，蛋白质还广泛用于化学，生物技术和医学 - 例如，作为胰岛素或洗衣粉中使用的生物催化剂等疗法或分解塑料。尽管它们具有显着的结构和功能多样性，但绝大多数蛋白质仅由20个标准构件，即规范氨基酸制成。这些氨基酸仅包含一组狭窄的功能基序，这最终限制了我们通过新功能开发蛋白质的能力。为了解决这一基本限制，已经开发了一种强大的蛋白质工程技术，称为遗传代码扩展（GCE），以允许蛋白质从> 20个氨基酸构建块中生产。现在，使用这种技术，可以选择将数百种具有新功能侧链的非经典氨基酸（NCAA）选择性地引入蛋白质中，从而导致新一代生物催化剂，高级材料和新的生物治疗学的发展。然而，尽管进步很大及其巨大的商业潜力，但现有的技术局限性阻碍了GCE从学术实验室转化为商业蛋白质产品。当前的翻译障碍包括含NCAA的蛋白质的低收益率以及对大量NCAA的需求，最终导致高昂的生产成本。在此建议中，我们将开发一个完全集成的工程生物学平台，以将GCE转化为商业应用。将来自学术界和行业的多学科研究人员汇总在一起，我们将开发能够生物合成新功能性NCAA的工程菌株，并有效地将其引入蛋白质中，以比现有平台相比以大大低的成本提供精确功能的蛋白质。为了体现我们的技术，我们将与我们的工业合作伙伴阿斯利康（Astrazeneca），gsk和prozomix合作，将我们的工程菌株应用于下一代生物催化剂和蛋白质疗法的大规模生产。展望未来，该提案中开发的多功能GCE平台和工程生物学工具将使各种功能化蛋白质的可扩展生产能够响应新兴的社会需求。