Research

Research of multifunctional compounds targeting neuroinflammation and cholinergic deficit in Alzheimer's disease

Code:

N1-0277

Range:

01. January 2023 - 31. December 2025

Range:

1.31 FTE

Leader:

Stanislav Gobec

Field:

1-09 Natural sciences and Mathematics - Pharmacy

Abstract:

Neurodegenerative diseases, including Alzheimer's disease (AD), pose a serious healthcare threat with the staggering number of patients diagnosed with these disorders. The therapy is currently limited to palliative care and relief of the symptoms with numerous novel drugs in the pipeline. Among these, multifunctional ligands are focused on targeting multiple pathologies involved in the AD progression. Simultaneous targeting of neuroinflammation via inhibition of p38α mitogen-activated pretein kinase (p38α MAP kinase) and cholinergic deficit via inhibition of butyrylcholinesterase is a novel, unaddressed approach, which will be undertaken in the project. To reach these goals multifunctional ligands inhibiting both enzymes will be designated, synthesized and evaluated using in silico, in vitro and in vivo methods to validate the project concept. New molecular tool compounds obtained in the project will not only add to our understanding of AD pathogenesis, but could also represent an excellent springboard for further development into an active pharmaceutical substance. At the end of the project we expect to yield 2-4 optimized lead compounds with balanced low-micromolar to nanomolar activities against p38α MAP kinase and butyrylcholinesterase. These compounds will have good in vitro activity in cellular models of neuroinflammation related to AD, procognitive properties at least comparable to those of reference drugs, good safety profile and the most benificial pharmacokinetic profile (e.g., high bioavailability and brain penetration, good plasma stability). They willl have potential to be progressed to further preclinical and clinical evaluations. The project consortium consists of three partners with different expertise and high complementarity of medical research in fields of medicinal chemistry, chemical biology and pharmacology. The partners are extensively focused on multifunctional ligands in the research of AD. In the project, the in depth expertise of partner institutions (University of Hradec Kralove (UHK) - organic chemistry, physico-chemical properties determination, recombinant protein production and purification; University of Ljubljana - Faculty of Pharmacy (UL-FFA) - in silico drug design, medicinal chemistry,organic chemistry, biochemistry, cell-based studies; Jagiellonian University Medical College (JUM) - in vivo pharmacological (pharmacodynamic and pharmacokinetic studies) will allow the consortium to reach the project objectives. Each partner will contribute equally to the project consortium, which will culminate in successful accomplishment of project goals.