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Synthesis and evaluation of antineurotoxicity properties of an amyloid-ß peptide targeting ligand containing a triamino acid.
Honcharenko, Dmytro; Bose, Partha Pratim; Maity, Jyotirmoy; Kurudenkandy, Firoz Roshan; Juneja, Alok; Flöistrup, Erik; Biverstål, Henrik; Johansson, Jan; Nilsson, Lennart; Fisahn, André; Strömberg, Roger.
Afiliación
  • Honcharenko D; Department of Biosciences and Nutrition, Karolinska Institutet, S-14183 Huddinge, Sweden. Roger.Stromberg@ki.se Dmytro.Honcharenko@ki.se.
Org Biomol Chem ; 12(34): 6684-93, 2014 Sep 14.
Article en En | MEDLINE | ID: mdl-25030615
ABSTRACT
Peptide-like compounds containing an arginine have been shown to bind and stabilize the central helix of the Alzheimer's disease related amyloidpeptide (Aß) in an α-helical conformation, thereby delaying its aggregation into cytotoxic species. Here we study a novel Aß 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 Aß-ligand interaction, and molecular dynamics (MD) simulation of the stability of the Aß central helix in the presence of the AEDabDab ligand shows further stabilization of the helical conformation of Aß 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 Aß neurotoxicity the AEDab triamino acid building block is synthesized by reductive alkylation of N-protected-glycinal with α-amino-protected diaminobutanoic acid, and the Aß 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 Aß1-42 induced reduction of gamma (γ) oscillations in hippocampal slice preparation.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Fragmentos de Péptidos / Péptidos beta-Amiloides / Agregación Patológica de Proteínas / Ritmo Gamma / Aminobutiratos / Hipocampo Límite: Animals Idioma: En Año: 2014 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Fragmentos de Péptidos / Péptidos beta-Amiloides / Agregación Patológica de Proteínas / Ritmo Gamma / Aminobutiratos / Hipocampo Límite: Animals Idioma: En Año: 2014 Tipo del documento: Article