Nucleoside-2′,3′/3′,5′-bis(thio)phosphate antioxidants are also capable of disassembly of amyloid beta₄₂-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 (Aβ)-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 Aβ₄₂-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 Aβ₄₂-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 Aβ₄₂-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 Aβ₄₂-Zn(ii) and Aβ₄₂-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 Aβ₄₂-M(ii) structure, back to that of the free Aβ₄₂. Finally, cryo-TEM and TEM images confirmed the disassembly of Aβ₄₂ and Aβ₄₂-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 Aβ₄₂-Cu(ii)/Zn(ii) aggregates.