Nucleoside-5 %26apos;-phosphorothioate analogues are biocompatible antioxidants dissolving efficiently amyloid beta-metal ion aggregates

作者：Amir Aviran; Shmuel Eran; Zagalsky Rostislav; Sayer Alon H; Nadel Yael; Fischer Bilha^*

来源：Dalton Transactions, 2012, 41(28): 8539-8549.

DOI：10.1039/c2dt30631j

Amyloid beta (A beta) peptide is known to precipitate and form aggregates with zinc and copper ions in vitro and, in vivo in Alzheimer%26apos;s disease (AD) patients. Metal-ion-chelation was suggested as therapy for the metal-ion-induced A beta aggregation, metal-ion overload, and oxidative stress. In a quest for biocompatible metal-ion chelators potentially useful for AD therapy, we tested a series of nucleoside 5%26apos;-phosphorothioate derivatives as re-solubilization agents of Cu+/Cu2+/Zn2+-induced A beta-aggregates, and inhibitors of Fenton reaction in Cu+ or Fe2+/H2O2 system. The most promising chelator in this series was found to be APCPP-gamma-S. This nucleotide was found to be more efficient than EDTA in re-solubilization of A beta(40)-Cu2+ aggregates as observed by the lower diameter, d(H), (86 vs. 64 nm, respectively) obtained in dynamic light scattering measurements. Likewise, APCPP-gamma-S dissolved A beta(40)-Cu+ and A beta(42)-Cu2+/Zn2+ aggregates, as monitored by H-1-NMR and turbidity assays, respectively. Furthermore, addition of APCPP-gamma-S to nine-day old A beta(40)-Cu2+/Zn2+ aggregates, resulted in size reduction as observed by transition electron microscopy (diameter reduction from 2.5 to 0.1 mu m for A beta(40)-Cu2+ aggregates). APCPP-gamma-S proved to be more efficient than ascorbic acid and GSH in reducing OH radical production in Fe2+/H2O2 system (IC50 values 85, 216 and, 92 mu M, respectively). Therefore, we propose APCPP-gamma-S as a potential AD therapy capable of both reducing OH radical production and re-solubilization of A beta(40/42)-Mn+ aggregates.

• 出版日期2012