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A new generation of ligands designed to interact with the α-helix/-strand discordant region of the amyloid- peptide (Aβ) and to counteract its oligomerization is presented. These ligands are designed to interact with and stabilize the Aβ central helix (residues 13-26) in an α-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 Aβ, i.e. "clamping" the target. Molecular dynamics (MD) simulations of the stability of the Aβ central helix in the presence of a set of second-generation ligands were performed and revealed further stabilization of the Aβ α-helical conformation, with larger number of polar and non-polar contacts between ligand and Aβ, compared to first-generation ligands. The synthesis of selected novel Aβ-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'-N,N-dimethylamino-1,8-naphthalimido group in the side chain. The ability of the ligands to reduce Aβ1-42 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 Aβ1-42 at a stoichiometric ratio.
This article was published in the following journal.
Name: ACS chemical neuroscience
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Compounds that are designed to mimic the 3D structure of a natural peptide or protein.
Peptides generated from AMYLOID BETA-PEPTIDES PRECURSOR. An amyloid fibrillar form of these peptides is the major component of amyloid plaques found in individuals with Alzheimer's disease and in aged individuals with trisomy 21 (DOWN SYNDROME). The peptide is found predominantly in the nervous system, but there have been reports of its presence in non-neural tissue.
A type of extracellularly deposited substance composed of an amyloid protein and additional components including HEPARAN SULFATE PROTEOGLYCAN; LAMININ; COLLAGEN TYPE IV; SERUM AMYLOID P-COMPONENT; and APOLIPOPROTEINS E which together form characteristic amyloid fibrils. The core of amyloid fibrils is formed by the stacking of overlapping beta-pleated sheet domains of the amyloid protein. There are many different amyloid proteins that have been found forming the core of the fibrils in vivo. However, amyloid can be formed from any protein that exposes beta-pleated strand conformations during unfolding or refolding. A common characteristic of amyloid is the ability to bind such dyes as CONGO RED and thioflavine.
Proteins that form the core of amyloid fibrils. For example, the core of amyloid A is formed from amyloid A protein, also known as serum amyloid A protein or SAA protein.
A pancreatic beta-cell hormone that is co-secreted with INSULIN. It displays an anorectic effect on nutrient metabolism by inhibiting gastric acid secretion, gastric emptying and postprandial GLUCAGON secretion. Islet amyloid polypeptide can fold into AMYLOID FIBRILS that have been found as a major constituent of pancreatic AMYLOID DEPOSITS.
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