Univerza na Primorskem Fakulteta za matematiko, naravoslovje in informacijske tehnologije
Več informacij o projektu / More info about the project
Vsebina projekta / Project content
Zaradi staranja prebivalstva se je povečalo tudi število bolnikov z boleznimi povezanimi s starostjo,
vključno z demenco. Alzheimerjeva bolezen (AB) je najpogostejša oblika starostne demence z več
kot 35 milijonov bolnikov po vsem svetu. Po napovedih svetovne zdravstvene organizacije se bo število
dementnih pacientov še naprej povečevalo in naj bi po pričakovanjih do leta 2050 doseglo številko vsaj
95 milijonov. Zdravila za zdravljenje demence samo lajšajo simptome bolezni, nimajo pa velikega
vpliva na zaviranje napredovanja AB, hkrati pa imajo tudi izrazite neželene stranske učinke. Za
zaustavitev napredovanja bolezni in morebitno ozdravitev pa nujno potrebujemo nove
učinkovine.
Etiologija AB še ni povsem pojasnjena. Poleg nastanka amiloidnih leh, sestavljenih iz agregiranega
amiloida beta (Aβ), so najbolj izrazite spremembe pri nevrodegeneraciji značilni za AB še povečan
oksidativni stres, porušena homeostaza kovinskih ionov, neravnovesje v nivojih monoaminskih živčnih
prenašalcev skupaj s povečano aktivnostjo MAO-B, in predvsem izrazito znižanje koncentracije
živčnega prenašalca acetilholina (ACh) v možganih. Tri od štirih trenutno registriranih zdravilnih
učinkovin za terapijo AB zavirajo holin esteraze (ChE) in s tem povečajo holinergični prenos v
prizadetih možganih ter omilijo znake bolezni. V možganih sta prisotni dve vrsti ChE. Acetilholin
esteraza (AChE) je odgovorna za 80% možganske holin esterazne aktivnosti in je specifična tarča
zgoraj omenjenih zdravilnih učinkovin. Najnovejša dognanja predstavljajo tudi butirilholin
esterazo (BChE) kot primerno terapevtsko tarčo, v luči vzdrževanja holinergične aktivnosti
in kognitivnih sposobnosti ob zmanjšanih neželenih stranskih učinkih.
Aβ peptidi naj bi bili tudi eden od vzrokov nastanka AB. Ti 39–43 aminokislinskih ostankov dolgi
peptidi se lahko uredijo v različne oligomerne in fibrilarne zvrsti, ki imajo različno stopnjo toksičnosti.
Veliko raziskav je usmerjenih v iskanje molekul, ki bi zavirale tendenco agregiranja teh peptidov.
Nastanek fibrilov Aβ vpliva na več molekularnih procesov AB, kot sta na primer oksidativni stres in
porušena homeostaza kovinskih ionov. Življenjsko pomembna kovinski ioni, kot so Fe , Zn i n
Cu , se ujamejo v komplekse z Aβ, kar se kaže tudi v visoki koncentraciji teh ionov v amiloidnih
plakih izoliranih iz možganov bolnikov z AB. Zaradi terapevtskega potenciala, je zelo obetaven
in nujen pristop razvoj multifunkcionalnih spojin, ki lahko specifično kelirajo kovinske ione,
zmanjšajo agregacijo Aβ ter inhibirajo BChE in MAO-B.
Cilj tega projekta je razvoj novih multifunkcionalnih spojin kot potencialnih novih zdravil za zdravljenje
AB. Načrtovane spojine bodo selektivno kelirale specifične kovinske ione, zavirale agregacijo Aβ ter
delovale kot zaviralci BChE in MAO-B. Z uporabo strukturno-podprtega načrtovanja bomo v eno
molekulo združili strukturne lastnosti, ki bodo omogočale vplivanje na različne patofiziološke procese,
značilne za AB. Pričakujemo, da bomo razvili vsaj 1–2 optimizirani spojini vodnici, ki bosta nizko
nanomolarna zaviralca BChE in bosta istočasno dobro kelirali kovinske ione ione, delovali
antioksidativno, ter zavirali agregacijo Aβ. Med projektom pridobljene optimizirane multifunkcionalne
spojine vodnice bodo predstavljale pomemben prispevek v iskanju spojin, ki bi lahko prešle v klinične
faze. Te spojine lahko predstavljajo dobro osnovo za nadaljnji razvoj novih zdravil za zdravljenje AB.
Rezultate raziskav bomo objavili v uglednih revijah z visokim faktorjem vpliva ter mednarodnih
patentnih prijavah. Skupni dosedanji raziskovalni dosežki vodje projekta ter ostalih partnerjev
dokazujejo, da je projekt izvedljiv, ter da je zagotovljena vsa potrebna infrastruktura za uspešno
izvedbo projekta. Predlagani projekt bo izkoristil obstoječo mednarodno mrežo sodelovanj. Dobro
vodenje projekta zagotavljajo tudi vodstvene izkušnje prof. Gobca (prodekan na Fakulteti za farmacijo
2005-2007, dekan na fakulteti za Farmacijo 2007-2011, vodja projektov v FP6 in FP7).
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 ADC-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 Fe , Zn and Cu ,
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.