Rationally Designed Cu(I) Ligand to Prevent CuAβ-Generated ROS Production in the Alzheimer's Disease Context

In the context of Alzheimer's disease, copper (Cu) can be loosely bound to the Amyloid-β (Aβ) peptide, leading to the formation of CuAβ, which can catalytically generate Reactive Oxygen Species that contribute to oxidative stress. To fight against this phenomenon, the chelation therapy approach has been developed and consists of using a ligand able to remove Cu from Aβ and to redox-silence it, thus stopping the Reactive Oxygen Species (ROS) production. A large number of Cu(II) chelators has been studied, allowing us to define and refine the properties required to design a "good" ligand, but without strong therapeutic outcomes to date. Those chelators targeted the Cu(II) redox state. Herein, we explore a parallel and relevant alternative pathway by designing a chelator able to target the Cu(I) redox state. To that end, we designed LH₂ ([1N3S] binding set) and demonstrated that (i) it is perfectly able to extract Cu(I) from Cu(I)Aβ even in the presence of an excess of Zn(II) and (ii) it redox-silences the Cu, preventing the formation of ROS. We showed that LH₂ that is sensitive to oxidation can efficiently replace the [Zn(II)L] complex without losing its excellent ability to stop the ROS production while increasing its resistance to oxidation.