Ghrelin de-acylation inhibitors as novel compounds for Parkinson's dementia

帕金森病（PD）是第二常见的神经退行性疾病，也是增长最快的神经系统疾病。大约每10名帕金森病患者中就有7人会迅速恶化为痴呆症。可以理解的是，失去记忆能力是PD患者最担心的问题之一。这一可怕的前景直接影响到确诊患者及其家庭，并产生深远的社会和经济影响。目前，对于医生来说，预防帕金森病痴呆症发展的选择很少。我们的目标是通过瞄准肠道中产生的一种因子来克服这一限制，我们发现这种因子在被诊断为PD痴呆的患者中是有缺陷的。这种肠道因子被称为胃饥饿素，有两种形式；我们的数据显示，一种形式在大脑中产生新的神经细胞，这对形成新的记忆和减少炎症至关重要。而另一种则有相反的效果——阻断这些重要细胞的形成，增加炎症。我们已经发现了一种小分子，它可以抑制产生有害形式的胃饥饿素的酶。这种工具化合物已被用于合理设计新的小分子，这些小分子具有改进的药物样特性，可以增加胃饥饿素的记忆增强和抗炎形式，同时降低胃饥饿素的有害版本的水平。在这个项目中，我们将合成这些新分子，并使用在斯旺西大学医学院和伦敦大学学院的阿尔茨海默病研究英国药物发现研究所开发的既定实验室分析来测试它们的抑制活性。我们的首要目标是研制一种治疗帕金森痴呆症的新型药物。

Parkinson's disease (PD) is the second most common neurodegenerative disease and is the fastest growing neurological condition. Approximately 7 in every 10 people with PD will rapidly deteriorate into dementia. Understandably, losing the ability to remember is one of the major concerns of individuals diagnosed with PD. This terrifying prospect directly affects those diagnosed as well as their families, and has far reaching societal and economic implications. At the moment, there are very few options for doctors to prevent the development of dementia in PD. We aim to overcome this limitation by targeting a factor produced in the gut that we show to be faulty in people diagnosed with PD dementia. This gut factor, called ghrelin, comes in two forms; our data shows that one form generates new nerve cells in the part of the brain that is essential for the formation of new memories and reduces inflammation. While the other has the opposite effect - blocking the formation of these important cells and increasing inflammation. We have identified a small molecule that inhibits the enzyme responsible for generating the harmful form of ghrelin. This tool compound has been used to rationally design new small molecules with improved drug-like characteristics that increase the memory boosting and anti-inflammatory form of ghrelin, whilst at the same time reducing the level of the harmful version of ghrelin. In this project, we will synthesise these new molecules and test their inhibitory activity using established laboratory assays developed at Swansea University Medical School and at the Alzheimer's Research UK Drug Discovery Institute at UCL. Our overarching aim is to make a new type of drug for the treatment of PD dementia.