Regulação da homeostasia de ferro, inflamação e metabolismo da dopamina na doença de Parkinson com a nova geração de fármacos modificadores de doença

In project RESTORE our aim is to develop a first-in-class drug candidate that can modulate the iron levels and related inflammatory events and regulate the DA levels in the brain. Accordingly, we will optimize the lead compounds obtained in project COMT4BRAIN based on hydroxypyridin-4-one and piperine by a fragment to lead optimization process to obtain bisubstrate COMT inhibitors. In that way we can obtain more potent COMT inhibitors and at the same time allow us to have extra positions for tailoring strategies. Then, the most effective COMT inhibitors will be tailored with moieties/fragments that ensure their role as modulators of ferroptosis and neuroinflammation. The libraries will be screened to assess for their ability to inhibit COMT and modulate ferroptosis and related inflammatory events. Additionally, we will evaluate the BBB permeability, cytotoxicity, and the drug-like profile of the best candidates. The outperforming candidate(s), with suitable safety and drug-like profiles, will be selected for in vivo studies in animal models. This proposal is highly innovative for the following reasons: a) drug design strategies for PD have largely overlooked the role of ferroptosis and related inflammatory events in the disease aetiology; b) no COMT inhibitor that can modulate ferroptosis and neuroinflammation has been developed yet; c) a new class of safe, effective, central COMT inhibitors can be developed. The current proposal is a follow-up of project COMT4BRAIN (POCI-01-0145-FEDER-029164), in which the present teams joined efforts and successfully discovered new leads that act as selective inhibitors of brain MB-COMT, the main isoform involved in DA metabolism in neurons. The RESTORE team has been conducting research in the area of Drug Discovery (Medicinal Chemistry, Pharmacology and Toxicology) for a long time. The cross-interdisciplinary and complementary backgrounds of the team researchers and consultants will be the driving force and assurance of the project success. The main outcomes of the proposal are the following: a) develop a first-in-class drug candidate that can modulate the excess iron and inflammatory events and regulate DA levels in the brain; b) feed the pipeline with new disease-modifying drug candidates for PD; c) patent the most promising candidate(s); d) knowledge transfer to pharmaceutical/biotech companies, namely those interested in the field of antiparkinsonians and therapeutic applications thereof; e) train undergraduate and graduate students and early stage researchers; f) disseminate innovative research in international, peer-review scientific journals and international conferences; g) increase the awareness for PD by disseminating our main results to the scientific community and to the society in general. This project fits the current line of research of the applicant and participant/collaborative institutions, which is focused on the drug discovery for neurological disorders. We expect this project to be a step forward in the development of a next-generation of disease-modifying drugs for PD.