An improved bioproduction system for proteins and small molecules

改进的蛋白质和小分子生物生产系统

基本信息

批准号：
BB/P010490/1
负责人：
Nicola Joan Patron
金额：
$ 58.54万
依托单位：
Earlham Institute
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FP010490%2F1
关键词：
improved bioproduction system proteins small

项目摘要

Global demand for quantities of vaccines and therapeutic molecules is growing. Plants, in particular, are the source of a great diversity of biologically active small molecules and a great many natural products found in plants are used as human therapies. However, these chemicals are often found in low abundance or are produced in species that are difficult to mass-cultivate requiring either chemical synthesis or the transfer of the genetic pathway to an alternative biological host in order to produce compounds at sufficient quantities. While microorganisms have proven to be exceptionally powerful for manufacturing therapies, some are not easily produced in high yields. There is particular interest in platforms that are able to respond rapidly to new disease threats, for example, the production of vaccines. Plants have been shown to be capable of efficient expression of therapeutic proteins and secondary metabolites. In a process commonly known as 'molecular pharming' plants have been demonstrated to be capable of producing a very large number of vaccine doses in just a few weeks. Gene expression can be complicated by the endogenous metabolism of the host diverting intermediates or performing unwanted modifications of expressed molecules. Much work has been done to tailor specific strains of bacteria and yeasts to increase production of compounds. However, to date, little effort has been spent on improving the plant production chassis, partly due to a lack of available tools. New technologies now allow us to take targeted approaches to modifying plant genes. We have identified genes expressed by the plant that are likely to be deleterious to heterologous bioproduction of small molecules. We will now make new lines of Nicotiana benthamiana, a relative of tobacco from Northern Australia, that are improved in their ability to produce small molecules of interest. We will then measure the impact of the changes that we have made by assessing the ability of our new lines to produce greater quantities of desirable new proteins and metabolites. This work will add to our knowledge of the metabolism of plants, helping us to understand how it responds to perturbation. It will also lead towards the production of plants that are genetically tailored for the production of different classes of therapeutic molecules

全球对疫苗和治疗分子量的需求正在增长。尤其是植物是生物活性小分子多样性的来源，在植物中发现的许多天然产物被用作人类疗法。但是，这些化学物质通常是在低丰度中发现的，或者是在需要化学合成或将遗传途径转移到替代生物学宿主的物种中产生的，以便以足够的量产生化合物。尽管事实证明，微生物对于制造疗法具有异常强大，但有些人不容易产生高产量。人们对能够对新的疾病威胁迅速反应的平台特别感兴趣，例如，疫苗的生产。植物已被证明能够有效地表达治疗蛋白和继发代谢物。在一个通常被称为“分子药物”植物的过程中，已经证明能够在短短几周内产生大量的疫苗剂量。宿主转移中间体的内源代谢或对表达分子进行不必要的修饰可能使基因表达变得复杂。为了量身定制细菌和酵母菌的特定菌株以增加化合物的产生。但是，迄今为止，几乎没有花费在改善植物生产机箱上，部分原因是缺乏可用的工具。现在，新技术使我们能够采用有针对性的方法来修饰植物基因。我们已经确定了由植物表达的基因，这些基因可能对小分子的异源生物生产有害。现在，我们将制作新的烟草本尼亚娜（Nicotiana Benthamiana），这是来自澳大利亚北部的烟草的亲戚，它们的产生小分子的能力得到了提高。然后，我们将通过评估新产品线产生更多理想的新蛋白质和代谢物的能力来衡量我们所做的变化的影响。这项工作将增加我们对植物代谢的了解，从而帮助我们了解其对扰动的反应。它还将导致生产用于生产不同类别的治疗分子的基因量身定制的植物