Opis projektu
Miedź celem leczenia w chorobie Alzheimera?
Choroba Alzheimera jest zaburzeniem neurodegeneracyjnym wywoływanym przez nadmierne gromadzenie się peptydu nazywanego beta-amyloidem. Nowe dowody naukowe wskazują, że jony metali, głównie miedzi i cynku, wiążą się z tym peptydem. Finansowany przez Europejską Radę ds. Badań Naukowych projekt aLzINK weryfikuje hipotezę, według której jony metali wpływają w pewien sposób na patofizjologię choroby Alzheimera. Kluczowym celem zespołu jest zbadanie podstawowych mechanizmów, charakteru wiązań i możliwego toksycznego wpływu analizowanych jonów metali. Naukowcy opracują nowe leki selektywnie celujące w miedź (zamiast cynku) związaną z beta-amyloidem, aby w ten sposób zakłócić jego szkodliwe działanie.
Cel
Alzheimer's disease (AD) is one of the most serious diseases mankind is now facing as its social and economical impacts are increasing fastly. AD is very complex and the amyloid-β (Aβ) peptide as well as metallic ions (mainly copper and zinc) have been linked to its aetiology. While the deleterious impact of Cu is widely acknowledged, intervention of Zn is certain but still needs to be figured out.
The main objective of the present proposal, which is strongly anchored in the bio-inorganic chemistry field at interface with spectroscopy and biochemistry, is to design, synthesize and study new drug candidates (ligands L) capable of (i) targeting Cu(II) bound to Aβ within the synaptic cleft, where Zn is co-localized and ultimately to develop Zn-driven Cu(II) removal from Aβ and (ii) disrupting the aberrant Cu(II)-Aβ interactions involved in ROS production and Aβ aggregation, two deleterious events in AD. The drug candidates will thus have high Cu(II) over Zn selectively to preserve the crucial physiological role of Zn in the neurotransmission process. Zn is always underestimated (if not completely neglected) in current therapeutic approaches targeting Cu(II) despite the known interference of Zn with Cu(II) binding.
To reach this objective, it is absolutely necessary to first understand the metal ions trafficking issues in presence of Aβ alone at a molecular level (i.e. without the drug candidates).This includes: (i) determination of Zn binding site to Aβ, impact on Aβ aggregation and cell toxicity, (ii) determination of the mutual influence of Zn and Cu to their coordination to Aβ, impact on Aβ aggregation, ROS production and cell toxicity.
Methods used will span from organic synthesis to studies of neuronal model cells, with a major contribution of a wide panel of spectroscopic techniques including NMR, EPR, mass spectrometry, fluorescence, UV-Vis, circular-dichroism, X-ray absorption spectroscopy...
Dziedzina nauki
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- natural scienceschemical sciencesinorganic chemistrybioinorganic chemistry
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesphysical sciencesopticsspectroscopyabsorption spectroscopy
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
Program(-y)
Temat(-y)
System finansowania
ERC-STG - Starting GrantInstytucja przyjmująca
75794 Paris
Francja