Descrizione del progetto
Colpire l’omeostasi dei metalli all’interno del cervello nel morbo di Alzheimer
Le prove accumulate indicano che la perdita di neuroni nel morbo di Alzheimer (AD, Alzheimer’s Disease) è il risultato di uno stress ossidativo dovuto a ioni metallici attivi, quali il rame, su diversi aggregati di peptidi di beta-amiloide. Attraverso molte sperimentazioni sul fallimento dei farmaci per l’AD, gli scienziati del progetto TS4NC, finanziato dall’UE, stanno ricorrendo alla regolazione dell’omeostasi dei metalli come opzione di trattamento. Gli agenti S4N multifunzionali rappresentano candidati promettenti, poiché non solo rimuovono il rame tramite chelazione dalle placche amiloidi e forniscono neuroprotezione, ma ridistribuiscono inoltre gli ioni di rame all’interno della circolazione fisiologica. L’approccio proposto da TS4NC dovrebbe contribuire a ripristinare l’omeostasi dei metalli nel cervello e aprire nuovi percorsi di sviluppo dei farmaci per l’AD.
Obiettivo
Despite enormous research efforts across academia and pharmaceutical industry, all clinical trials over the last decade have failed in finding a treatment for Alzheimer’s Disease (AD) which remains one of the greatest challenges in drug discovery. Taking consideration all together three prevailing AD hypotheses: Amyloid Cascade, Metal Ions and Oxidative Stress, researchers conclude that loss of neurons is due to a high level of oxidative stress produced by nonregulated redox active metal ions such as copper linked to different forms/aggregates of amyloid-β (Aβ) peptides. Therefore, the regulation of metal homeostasis is a key target for drug development. Herein, we propose a new class of multifunctional agents – S4Ns, which not only sequester Cu ions from their Aβ complexes and arrest their redox cycles, thus reduce oxidative stress in the neuronal cells, inhibit Aβ aggregation, inhibit neuroglia activation and provide anti-inflammatory effects, delivering overall neuroprotection, but also put Cu back into normal physiological circulation by releasing Cu to natural Cu-carriers. The key novelty of this approach lies in that S4N mimics the N-terminus of Aβ4-x peptide (ATCUN motif), providing 4N square planar Cu(II) coordination with high affinity and selectivity. In general, S4Ns do not act as traditional chelating agents by simply eliminating metals from the organism, on the contrary they perform as Metal–Protein Attenuating Compounds (MPACs) by redistributing and assisting in the restoration of brain biometal homeostasis. This synergistic but novel strategy will allow us to carry out a comprehensive study of the new compounds and shed light into discovering promising drug candidate. Of equally importance, TS4NC MCSA will open new research horizons and significantly boost scientific career of the applicant, by helping her to reach professional maturity during the fellowship.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinatore
SW7 2AZ LONDON
Regno Unito