title: Synthesis and evaluation of antineurotoxicity properties of an amyloid-β peptide targeting ligand containing a triamino acid.
abstract: Peptide-like compounds containing an arginine have been shown to bind and stabilize the central helix of the Alzheimer's disease related amyloid-β peptide (Aβ) in an α-helical conformation, thereby delaying its aggregation into cytotoxic species. Here we study a novel Aβ targeting ligand AEDabDab containing the triamino acid, N(γ)-(2-aminoethyl)-2,4-diaminobutanoic (AEDab) acid. The new AEDab triamino acid carries an extra positive charge in the side chain and is designed to be incorporated into a ligand AEDabDab where the AEDab replaces an arginine moiety in a previously developed ligand Pep1b. This is done in order to increase the Aβ-ligand interaction, and molecular dynamics (MD) simulation of the stability of the Aβ central helix in the presence of the AEDabDab ligand shows further stabilization of the helical conformation of Aβ compared to the previously reported Pep1b as well as compared to the AEOrnDab ligand containing an N(δ)-(2-aminoethyl)-2,5-diaminopentanoic acid unit which has an additional methylene group. To evaluate the effect of the AEDabDab ligand on the Aβ neurotoxicity the AEDab triamino acid building block is synthesized by reductive alkylation of N-protected-glycinal with α-amino-protected diaminobutanoic acid, and the Aβ targeting ligand AEDabDab is prepared by solid-phase synthesis starting with attachment of glutarate to the Wang support. Replacement of the arginine residue by the AEDab triamino acid resulted in an improved capability of the ligand to prevent the Aβ1-42 induced reduction of gamma (γ) oscillations in hippocampal slice preparation.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, S-14183 Huddinge, Sweden. Roger.Stromberg@ki.se Dmytro.Honcharenko@ki.se.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Honcharenko
authors.forename: Partha Pratim
authors.initials: PP
authors.lastname: Bose
authors.forename: Jyotirmoy
authors.initials: J
authors.lastname: Maity
authors.forename: Firoz Roshan
authors.initials: FR
authors.lastname: Kurudenkandy
authors.forename: Alok
authors.initials: A
authors.lastname: Juneja
authors.forename: Erik
authors.initials: E
authors.lastname: Flöistrup
authors.forename: Henrik
authors.initials: H
authors.lastname: Biverstål
authors.forename: Jan
authors.initials: J
authors.lastname: Johansson
authors.forename: Lennart
authors.initials: L
authors.lastname: Nilsson
authors.forename: André
authors.initials: A
authors.lastname: Fisahn
authors.forename: Roger
authors.initials: R
authors.lastname: Strömberg
mesh_terms: D000613:Aminobutyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000633:toxicity; D000818:Animals; D001120:Arginine / Q000737:chemistry; D065818:Gamma Rhythm / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D007608:Kainic Acid / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D056004:Molecular Dynamics Simulation; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000633:toxicity; D066263:Protein Aggregation, Pathological / Q000517:prevention & control*; D011485:Protein Binding; D055550:Protein Stability / Q000187:drug effects; D017433:Protein Structure, Secondary; D046509:Tissue Culture Techniques
chemical_list: D000613:Aminobutyrates; D016229:Amyloid beta-Peptides; D008024:Ligands; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D001120:Arginine; D007608:Kainic Acid