Role of PTA in the prevention of Cu(Amyloid-β) induced ROS formation and Amyloid-β oligomerisation in the presence of Zn

Elena Atrián-Blasco (1, 2) , Elena Cerrada (2) , Peter Faller (1, 3) , M. Laguna (2) , Christelle Hureau (1)

1 LCC - Laboratoire de chimie de coordination
2 Instituto de Síntesis Química y Catálisis Homogénea
3 Institut de Chimie de Strasbourg

Metal-targeting drugs are being widely explored as a possible treatment of Alzheimer’s disease, but most of these ligands are developed to coordinate Cu(II). In a previous communication (Metallomics, 2015, 7, 1229) we have shown another strategy where Cu(I) was targeted with the PTA (1,3,5-triaza-7-phosphaadamantane) ligand that is in addition able to target Cu(II) as well, reduce it and keep it in a safe complexed species. Removal of Cu(II) from the amyloid-β peptide prevents the stabilization of oligomers and protofibrils and the complexation of Cu(I) also stops the formation of reactive oxygen species. Besides, the presence of zinc, which is found in the synaptic cleft in higher concentration than copper, can hamper the ability of metal-targeting drug candidates, an issue that is still poorly considered and studied. Here we show that PTA fully keeps the above described properties even in presence of zinc, thus fulfilling an additional pre-requisite for its use as a model of Cu(I)-targetting drug candidates in the Alzheimer’s disease context.

Domaines: Chimie; Chimie de coordination

Elena Atrián-Blasco, Elena Cerrada, Peter Faller, M. Laguna, Christelle Hureau. Role of PTA in the prevention of Cu(Amyloid-β) induced ROS formation and Amyloid-β oligomerisation in the presence of Zn. Metallomics, 2019, 11 (6), pp.1154-1161. ⟨10.1039/C9MT00011A⟩. ⟨hal-02108487⟩