Development of Bioactive Molecules for Neurodegenerative Diseases Treatment – BioMol4ND

Project head: Anita Bosak

Project participants:

Ana Matošević, Dejan Opsenica, Suzana Žunec, Katarina Komatović, Sandra Šegan, Antonio Zandona, Zrinka Kovarik

Duration: 1 january 2021 – 31 December 2024

Funding: 1,000,000.00 HRK

Summary

The primary goal of the project is to develop molecules with the potential to alleviate the symptoms and slow down the progression of neurodegenerative diseases (ND) that primarily affect the neurons in the human brain that causes problems with movement and/or mental functioning. The project aims to rationally design dual site binding cholinesterase (ChE) inhibitors (acting on improving the acetylcholine level in the brain and on A aggregation) and use them as starting points for multitarget-directed ligand (MTDL) design by adding an additional pharmacophore in a single molecule entity able to act on other hallmarks of Alzheimer’s type of dementia (e.g. oxidative stress and bimetal dyshomeostasis). Compounds will be biologically evaluated (BACE1 and A-aggregation inhibition, pro-oxidant/antioxidant capacity, cytotoxicity, etc.) to determine their ability as possible drugs for treatment of ND. The development of these designed compounds will have two major objectives: development of CNS active and development of peripherally active compounds, depending on their ability to cross the blood-brain-barrier. In ND treatment, the development of multitargeted drugs is favourable compared to single-targeted drugs since an additional pharmacological response that might synergistically modulate the pathological cascade in neurodegeneration occurs. Moreover, current treatment of AD often combines currently available drugs, or of does so alongside an additional one acting on other hallmarks of ND (e.g. metal chelators). Considering that the AD type of dementia generally affects people ˃ 65, the use of a large number of drugs is a major burden for organism homeostasis. Considering the large number of patients that could bring a heavy burden to public health system in the future, the drugs that could alleviate or remove symptoms of dementia, allowing patients to be independent of the help from other people in daily life is very much needed.