Engineering saponin biosynthesis pathways for bio-production of novel vaccine adjuants

植物是药物和其他高价值化合物的丰富来源。在十九世纪，化学的进步使许多具有生物活性的天然产物能够从植物中提纯并确定其结构，为制药工业的出现铺平了道路。第一个商业化的天然纯药物是1826年从鸦片默克中提取的吗啡。随后，人们努力通过化学合成来制造天然产物，第一个例子是1899年拜耳商业化生产的水杨酸。然而，尽管取得了这些和其他方面的成功，但由于获取来源物种、提纯化合物和化学合成的挑战，绝大多数植物代谢多样性仍然没有得到开发。通过对植物的转录本和/或基因组进行测序来破译植物的化学潜力，然后将这些信息用作制造药物和其他高价值化学品的说明手册的能力，正在为利用植物王国巨大的化学多样性开辟新的途径。我们已经建立了用于快速重建植物代谢途径的瞬时植物表达技术，并证明该系统可以用于获取克级规模的产物。这项技术很容易推广，并已用于疫苗的商业生产。该项目旨在证明，以植物为基础的代谢工程是药物(和其他高价值化合物)商业化生产的可行途径，也是产生分子多样性和新产品发现的可靠平台。拟议工作的重点是设计皂素生物合成途径，用于新型疫苗佐剂的生物生产。这些成果有可能扩大现有佐剂的多样性，扩大整个疫苗行业的资源和能力，造福于该行业和社会。

Plants are a rich source of drugs and other high-value compounds. During the nineteenth century, advances in chemistry enabled many bioactive natural products to be purified from plants and their structures determined, paving the way for the emergence of the pharmaceutical industry. The first naturally derived pure medicine to be commercialized was morphine, extracted from opium Merck in 1826. Subsequently efforts were made to make natural products by chemical synthesis, the first example being salicylic acid, produced commercially by Bayer in 1899. However, despite these and other successes, the vast majority of plant metabolic diversity has remained untapped due to the problems of accessing source species, purifying compounds and the challenges of chemical synthesis. The ability to decode the chemical potential of plants by sequencing their transcriptomes and/or genomes and to then use this information as an instruction manual to make drugs and other high-value chemicals is opening up new routes to harness the vast chemical diversity of the Plant Kingdom. We have established transient plant expression technology for the rapid reconstruction of plant metabolic pathways and demonstrated that this system can be used to access gram-scale quantities of products. This technology is readily scalable and has been used for commercial production of vaccines. This project is intended to demonstrate that plant-based metabolic engineering is a viable route to the commercial production of pharmaceuticals (and other high-value compounds), and also a credible platform for the generation of molecular diversity and new product discovery. The focus of the proposed work is on engineering saponin biosynthesis pathways for bio-production of novel vaccine adjuvants. The outputs have the potential to broaden the diversity of available adjuvants and expand the resources and the capabilities of the vaccines industry as a whole, to the benefit of the industry and society.