The plant IPCS as a novel herbicide target

需要集约农业才能从日益减少的土地储备中提供足够的食物，以养活不断增长的世界人口并为其提供燃料。在这方面，作物保护方法，包括使用除草剂控制杂草发挥了重要作用，抗除草剂杂草的进化对现代农业构成了重大威胁。由于重复使用具有相同作用部位的除草剂，选择压力很大，因此抗药性经常成为一个问题。虽然这种压力可以通过作物和除草剂轮作来缓解，但允许使用的除草剂数量正在减少，因此迫切需要新的作用模式。杜伦大学最近的研究表明，参与鞘磷脂生物合成的肌醇磷酸神经酰胺合成酶(IPCS)可能是一个新的除草剂靶标。来自拟南芥和水稻的同源基因在达勒姆被分离和鉴定，并在法兰克福的拜耳进行了10,000种化合物的中等吞吐量筛选。通过这个筛选，我们能够确定几个有趣的具有体外和体内活性的先导结构。本项目将结合分子生物学、酶学、合成化学和基因组技术，进一步探索IPCS作为新型除草剂的新作用模式。更具体地说，我们的目标是实现以下目标：IPCS作为除草靶标的遗传学验证表明，除草活性和生化活性通过代谢和脂类特征相关，通过筛选HITS的密切类似物建立SAR，并合成新结构以提高抑制剂效力和除草效率(并将细胞毒性降至最低)。

Intensive agriculture is required to provide sufficient food from a diminishing land bank to feed and fuel a growing world population. In this context, crop protection methodologies, including the use of herbicides to control weeds play an important role and the evolution of herbicide resistant weeds represents a major threat to modern agriculture. Resistance often becomes a problem because of high selection pressure as a result of repeated use of herbicides with the same site of action. Whilst such pressures can be alleviated by crop and herbicide rotations the pool of permitted herbicides is decreasing and there is a major need for new modes of action.Recent work at Durham University has shown that inositol phosphorylceramide synthase (IPCS), an enzyme involved in sphingolipid biosynthesis, may represent a new herbicide target. Orthologues from Arabidopsis thaliana and rice were isolated and characterized at Durham and a medium throughput screen of 10,000 compounds was performed at BAYER, Frankfurt. From this screen we were able to identify several interesting lead structures with both in vitro and in vivo activity.This project will build upon these results by using a combination of molecular biology, enzymology, synthetic chemistry and omic technologies to further explore IPCS as a new mode of action for novel herbicides. More specifically, we aim to achieve the following:Genetic validation of IPCS as a herbicidal target Show that the herbicidal and biochemical activities are related though metabolomic and lipidomic profiling Establish SAR by screening close analoges of hits and synthesise new structures to improve inhibitor potency and herbicidal efficacy (and to minimize cytotoxicity).