Projects / Programmes
Development of multifunctional compounds for treatment of Alzheimer's disease
| Code |
Science |
Field |
Subfield |
| 1.09.00 |
Natural sciences and mathematics |
Pharmacy |
|
| Code |
Science |
Field |
| B740 |
Biomedical sciences |
Pharmacological sciences, pharmacognosy, pharmacy, toxicology |
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
Alzheimer's disease; drug discovery; structure-based drug design; multifunctional ligands.
Researchers (16)
Organisations (4)
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. In addition, the leadership experience of PI Gobec (Vice-Dean, Faculty of Pharmacy, 2005-2007; Dean of Faculty 2007-2011, project leader for FP6 and FP7 projects) will assure optimal coordination and running of the Project
Significance for science
Importance of the proposed research project for the development of science resides in (i) discovery of novel drugs in important therapeutic area and in (ii) development of methods for drug design, synthesis and study of their molecular mechanism of action. The research project is expected to give an important contribution to discovery of innovative drugs for treatment of Alzheimer disease with novel mechanisms of action. Due to ageing of the population, the expected number of Alzheimer disease patiens will increase in the future and this represents a serious global chalange for drug discovery science. Currently, there is no drug available to treat the causes of Alzheimer disease. It is therefore very important that academic research groups intensify their research toward new drugs and perform the pre-clinical steps of anti-Alzheimer drug discovery that can be then progressed further together with the industry.
Within the research project, important drug discovery tools will be used and developed in close collaboration with Slovene and international partners:
Rational design and synthesis of new lead compounds and potential drugs;
Computational methods for structure-based drug design;
Structure-based design of multitarget-directed ligands;
De novo design of new enzyme inhibitors;
Development and optimisation of new synthetic methods (including, but not limited to parallel synthesis, microwave-assisted synthesis, use of modern catalysts);
Development of simple and rapid methods for biochemical evaluation of enzyme inhibitors (drug candidates).
A special emphasis will be given to the application of the abovementioned tools in the field of neurodegenerative drug discovery.
Significance for the country
Discovery of novel innovative drugs and introducing them to the market in cooperation with strategic partners is a way to assure a sustained growth to Slovenian pharmaceutical industry which is currently one of major players in the Slovenian economy. The current generic nature of the Slovenian pharmaceutical industry does not preclude its evolution into research-oriented industry and education of scientists in a research project like this one will importantly contribute to this important socio-economic task. Novel drug molecules and lead compounds resulting from the proposed research project will be a good starting point for development of innovative medicines in cooperation of the Slovenian and international pharmaceutical industry. However, the knowledge about discovery of new anti-Alzheimer's agents relevant for this project is important also for generic pharmaceutical industry. Researchers, which will participate in the proposed research project, will gain competences for autonomous creative work in pharmaceutical industry, where they will create novel research focuses. This is especially important due to ongoing globalization of Slovenian pharmaceutical industry (such as merger of Lek d.d. with Novartis).
Acquired knowledge and skills of the participating researchers will enable them to competently work in the relevant professional positions of the research laboratories of multinational companies. This will consolidate the position of Slovenian science and industry in the world.
The participating researchers will be also perfectly trained for research work at university, other research institutes and governmental agencies. The proposed research programme will generate new and master the existing knowledge both of which are of paramount importance for sustained development of pharmaceutical industry and drug – oriented research in Slovenia. Fostering scientific excellence, which is one of major goals of the proposed research project, will contribute to affirmation of Slovenian science through publications in leading scientific journals. This will contribute to creation and preservation of the country's national identity in Europe and in the world. The proposed research project will create important new knowledge in fight against Alzheimer's disease. The results of the proposed research project will benefit the pharmaceutical industry, or will form the basis for the establishment of a start-up company.
Most important scientific results
Interim report,
final report
Most important socioeconomically and culturally relevant results
Interim report,
final report
