During aLzINK project, we have worked on the study at the molecular level of the processes at play between copper, zinc and the Aβ peptides in link with AD, with the final aim to deliver guidelines for the design of new sucessful drugs.
First, the description of the binding sites of metal ions (copper or zinc) to Aβ peptides of biologically relevant sequences (familial or murine mutants, N-term truncated peptides) have been completed. Elucidation of the zinc sites to the human and murine Aβ and as a function of pH were solved (Alies, CEJ 2018 & IC 2016). Evaluation of Cu(II) binding affinity to Aβ was performed using a new method (Conte-Daban, AC 2017). A review (Atrian, CCR 2018) and a book chapter (del Barrio, 2017) were written to recapitulate the state-of-the art of metal ions binding to amyloid-forming peptides (including Aβ). In addition, a review on the biological importance of N-term truncated Aβ was delivered (Borghesani, EJIC 2017).
A second part focused on the Cu(Aβ) complex responsible for ROS production. To perfectly describe this state, now called "in-between state", several studies were necessary (Cheignon, DT 2016 & Metallomics, 2016 & CS 2017; Atrian-Blasco, AC 2018). This is a key result because the way the Cu(Aβ) complex is able to produce ROS is likely to be the same for other intrinsically disordered peptides involved in pathologies. The elucidation of the paths by which Cu(Aβ) produces ROS evidenced that in addition to the stable Cu(Aβ) complexes (either in +I or +II redox states) the "in-between state" is also an important therapeutic target. This ROS production mechanism as well as other processes linking Aβ to oxidative stress in AD has been reviewed in Cheignon, RB 2018.
A third part was dedicated to investigations on the role of metal ions in the modulation of the Aβ self-assembly ability. A huge effort was necessary to get reproducible assembly data. This was reviewed in Faller, Front. Chem. 2021. While research papers on the impact of Cu and/or Zn on Aβ self-assembly are currently in the writting process, we have studied the co-assembly of the Aβ peptide with its N-term truncated counterpart, in presence of Cu(II) (Stefaniak, Chem. Eur. J., 2021) or Zn(II). This is the first paper where the co-assembly of two amyloid-forming peptides in presence of metal ions, known as modulators of the self-assembly, was reported. In addition, we have also worked to new Ln-based probes of the assembly (Madjoub, Chem. Eur.J. 2021) and review new possible lines of research with respect to assembly of amyloid-forming peptides in Ayala, ACN 2019. The Aβ-related toxicity in line with its participation to oxidative stress and formation of amyloid deposits was reviewed in a book chapter (Hureau, 2022).
The last part aimed at the design of new drug canditates with respect to chelation-based therapies. In this part, we have obtained many results. We have illustrated the importance of Zinc into the removal of Copper form the Aβ peptide (Conte-Daban, DT 2016, Atrian-Blasco, DT 2017, Zhang, CEJ 2018, Atrian-Blasco, Metallomics, 2019). That was one of the main objectives of aLzINK. In addition, we demonstrated that targeting Cu(I) is a very interesting option, although overlooked in the literature (Atrian, Metallomics, 2015 & 2019, Conte-Daban, CEJ 2017, Atrian-Blasco, CSR 2017), while Cu(I) could interfere in the detoxification of Cu(II) by Cu(II)-specific chelators (Esmieu, CEJ 2021 & IC 2021, Drommi, Molecules, 2022). We have also shown that kinetic aspects must be taken into account in the design of Cu(II) chelator, beyond the classical thermodynamic-only considerations of the equilibria at play (Conte-Daban, CEJ 2018). New kind of ligands (peptoid and polyoxometallates) were also used for the first time to remove Cu(II) from Aβ and stop the associated ROS formation (Behar, ANIE 2021 & Atrian, CC 2022) while the benefit of using Mn-based prodrug (Conte-Daban, CEJ 2017) was also proven. More concepts have to be published, where peptide ligands with interesting binding features (Gonzales, CEJ 2017, CC 2019, Beuning, IC 2021) are under focus. These chelating concepts and others from the literature were rewieved in Esmieu, IC 2019), while a global review on the metal ions/Aβ/chelator-based drug candidates was published in Hureau, EICB, 2018.
In addition to dissemination of the results towards an academic audience, a special input has been given to dissemination to a wide general audience.
