Nucleoside-2 ',3 '/3 ',5 '-bis(thio) phosphate antioxidants are also capable of disassembly of amyloid beta(42)-Zn(II)/Cu(II) aggregates via Zn(II)/Cu(II)-chelation

Currently, there is an urgent need for biocompatible metal-ion chelators capable of antioxidant activity and disassembly of amyloid beta (A beta)-aggregates as potential therapeutics for Alzheimer's disease (AD). We recently demonstrated the promising antioxidant activity of adenine/guanine 2',3' or 3',5'-bis(thio) phosphate analogues, 2'-dA/G3'5' PO/S and A2'3'PO/S, and their affinity to Zn(II)-ions. These findings encouraged us to evaluate them as agents for the dissolution of A beta(42)-Zn(II)/Cu(II) aggregates. Specifically, we explored their ability to bind Cu(II)/Zn(II)-ions, the geometry and stoichiometry of these complexes, Cu(II)/Zn(II)-binding-sites and binding mode, and the ability of these analogues to dissolve A beta(42)-Zn(II)/Cu(II) aggregates, as well as their effect on the secondary structure of those aggregates. Finally, we identified the most promising agents for dissolution of A beta(42)-Zn(II)/Cu(II) aggregates. Specifically, we observed the formation of a 1 : 1 complex between 2'-dG3'5'PO and Cu(II), involving O4 ligands. Zn(II) was coordinated by both thiophosphate groups of 2'-dA3'5'PS and A2'3'PS involving O2S2 ligands in a 1 : 1 stoichiometry. A2'3'PS dissolves A beta(42)-Zn(II) and A beta(42)-Cu(II) aggregates as effectively as, and 2.5-fold more effectively than EDTA, respectively. Furthermore, 2'-dG3'5' PS and A2'3'PS reverted the A beta(42)-M(II) structure, back to that of the free A beta(42). Finally, cryo-TEM and TEM images confirmed the disassembly of A beta(42) and A beta(42)-M(II) aggregates by A2'3'PS. Hence, 2'-dG3'5' PS and A2'3'PS may serve as promising scaffolds for new AD therapeutics, acting as both effective antioxidants and agents for solubilization of A beta(42)-Cu(II)/Zn(II) aggregates.