Research

Development of multifunctional compounds for treatment of Alzheimer's disease

Code:

L1-8157

Range:

30. April 2017 - 30. April 2020

Range:

0,61 FTE

Leader:

Stanislav Gobec

Field:

1-09 Natural sciences and Mathematics - Pharmacy

Abstract:

The ageing of the population has resulted in an increase in the number of people with age-related diseases such as dementia. With more than 35 million people affected worldwide, Alzheimer’s disease (AD) is the most prominent form of senile dementia. The number of patients afflicted with this progressive neurodegenerative disorder will continue to grow and is expected to reach 95 million by 2050. While ameliorating the symptoms of AD for only a couple of years with little effect on disease progression, currently available anti-AD drugs also have strong adverse effects. New drugs are urgently needed to delay further the progression of AD and possibly cure the disease.
The aetiology of AD is not entirely understood. Conditions that are known to participate in the AD-associated neurodegeneration include aggregation and accumulation of amyloid-β (Aβ) deposits, oxidative stress, loss of metal ion homeostasis, dysregulation of monoamine transmitters together with elevated activity of monoamine oxidase B (MAO-B), and a severe decrease in neurotransmitter acetylcholine (ACh) brain levels. Accordingly, three out of the four currently approved anti-AD drugs exploit cholinesterase (ChE) inhibition, with view to restore cholinergic activity. Two forms of ChEs are present in the brain. Acetylcholinesterase (AChE) accounts for 80% ChE activity and is the specific target of the above-mentioned drugs. However, recent data propose butyrylcholinesterase (BChE) as a viable therapeutic target for restoring cholinergic activity and improving cognitive performance, while minimizing the surge of adverse effects.
Aβ peptides have been proposed as causative of AD. These 39–43-residue-long Aβ peptides can assemble into a variety of oligomeric and fibrous species that have different levels of toxicity. Finding molecules that reduce the propensity of these Aβ peptides to aggregate is therefore a matter of active research. Aβ fibril formation affects several molecular processes in AD, as it can result in oxidative stress and loss of metal-ion homeostasis. The essential metal ions, such as Fe2+, Zn2+ and Cu2+, co-localize with the various Aβ structures in AD-affected brain. Increased activity of MAO-B in AD brain also contributes to oxidative stress and imbalance in monoamine neurotransmitters levels. Therefore, the development of multifunctional compounds that can chelate specific metal ions, reduce Aβ aggregation, and inhibit BChE and MAO-B is of major therapeutic interest.
The specific aim of this project is to develop new multifunctional compounds with the potential to be developed into novel anti-AD agents. The designed compounds will be able to selectively chelate specific metal ions, reduce Aβ aggregation, and inhibit MAO-B and BChE. Using structure-based drug design techniques and by merging several structural features into a single chemical entity, we will impinge upon the different processes associated with AD. We expect to develop 1–2 advanced lead compounds with low-nanomolar activities against BChE and MAO-B, good metal chelation chelation, antioxidative and Aβ anti-aggregation properties. Optimized lead multifunctional compounds developed in this project will provide a valuable contribution in pursuit of a clinical candidate; the latter will represent an important foundation for further development into active pharmaceutical substance.
The results of the Project will be published in high-ranking journals and be the subject of international patent applications. Through their recent joint research achievements, the Project PI and the team members have demonstrated that the Project is feasible and that all of required equipment is available. The Project will take advantage of the existing network of international collaboration.