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.
Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel. bilha.fischer@biu.ac.il.
Bosmat Levi
BL
Hevroni
Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel.
Dan Thomas
DT
Major
Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel.
Mudit
M
Dixit
Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel.
Anil Ranu
AR
Mhashal
Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel.
Susanta
S
Das
Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel. bilha.fischer@biu.ac.il.
Bilha
B
Fischer
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000737:chemistry*; D009705:Nucleosides / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry*; D010710:Phosphates / Q000737:chemistry* / Q000494:pharmacology*; D066329:Protein Aggregates / Q000187:drug effects*; D015032:Zinc / Q000737:chemistry*
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002614:Chelating Agents; D009705:Nucleosides; D010446:Peptide Fragments; D010710:Phosphates; D066329:Protein Aggregates; C075222:amyloid beta-protein (1-42); D003300:Copper; D015032:Zinc