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

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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.