%0 Journal Article
%T Amyloid-¦Â Peptide Targeting Peptidomimetics for Prevention of Neurotoxicity
%J -
%D 2019
%R https://doi.org/10.1021/acschemneuro.8b00485
%X A new generation of ligands designed to interact with the ¦Á-helix/¦Â-strand discordant region of the amyloid-¦Â peptide (A¦Â) and to counteract its oligomerization is presented. These ligands are designed to interact with and stabilize the A¦Â central helix (residues 13¨C26) in an ¦Á-helical conformation with increased interaction by combining properties of several first-generation ligands. The new peptide-like ligands aim at extended hydrophobic and polar contacts across the central part of the A¦Â, that is, ¡°clamping¡± the target. Molecular dynamics (MD) simulations of the stability of the A¦Â central helix in the presence of a set of second-generation ligands were performed and revealed further stabilization of the A¦Â ¦Á-helical conformation, with larger number of polar and nonpolar contacts between ligand and A¦Â, compared to first-generation ligands. The synthesis of selected novel A¦Â-targeting ligands was performed in solution via an active ester coupling approach or on solid-phase using an Fmoc chemistry protocol. This included incorporation of aliphatic hydrocarbon moieties, a branched triamino acid with an aliphatic hydrocarbon tail, and an amino acid with a 4¡ä-N,N-dimethylamino-1,8-naphthalimido group in the side chain. The ability of the ligands to reduce A¦Â1¨C42 neurotoxicity was evaluated by gamma oscillation experiments in hippocampal slice preparations. The ¡°clamping¡± second-generation ligands were found to be effective antineurotoxicity agents and strongly prevented the degradation of gamma oscillations by physiological concentration of monomeric A¦Â1¨C42 at a stoichiometric ratio
%U https://pubs.acs.org/doi/10.1021/acschemneuro.8b00485