A rational design to create hybrid β-sheet breaker peptides to inhibit aggregation and toxicity of amyloid-β
| Autor: | Gijs Schaftenaar, Marcel M. Verbeek, Floris L. van Delft, Anna Karawajczyk, Ilona B. Bruinsma, Robert M.W. de Waal |
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| Rok vydání: | 2011 |
| Předmět: |
Chemical and physical biology [NCMLS 7]
Molecular model Bioinformatics Beta sheet Pharmaceutical Science Synthetic Organic Chemistry Neuroinformatics [DCN 3] Fibril Biochemistry 03 medical and health sciences 0302 clinical medicine Solid-phase synthesis Translational research [ONCOL 3] Drug Discovery Senile plaques Viability assay GeneralLiterature_REFERENCE(e.g. dictionaries encyclopedias glossaries) 030304 developmental biology Pharmacology 0303 health sciences Chemistry Ligand Organic Chemistry Rational design Molecular Medicine Functional Neurogenomics [DCN 2] 030217 neurology & neurosurgery |
| Zdroj: | Medchemcomm, 2, 60-64 Medchemcomm, 2, 1, pp. 60-64 |
| ISSN: | 2040-2511 2040-2503 |
| Popis: | Alzheimer's disease is characterized by deposits of the amyloid β protein (Aβ) in the form of senile plaques and cerebral amyloid angiopathy. Deposition of Aβ into these pathological lesions is directed by step-wise aggregation of Aβ into oligomers, protofibrils and mature fibrils. Currently, all therapies are purely symptom-relieving, and an actual treatment or prevention of AD is still lacking. Since aggregated forms of Aβ are particularly neurotoxic, interference with the process of Aβ aggregation is a long-envisioned target for therapy. Based on the knowledge that both sulfated (macro)molecules and small synthetic peptides interfere with Aβ aggregation, we developed hybrid ligands to target Aβ fibrillization by a combination of peptide-peptide and sulfate-peptide interactions. A series of peptides, modified at the N-terminus with sulfated linkers, was successfully prepared by solid phase synthesis. The hybrid ligands were tested using a viability assay and an aggregation assay. Molecular modeling was applied to explain the binding of the hybrid ligands to Aβ42. The hybrid ligands that we designed, synthesized and evaluated were found to be non-toxic to cells but displayed negligible inhibition of Aβ fibrillization and Aβ-mediated cytotoxicity compared to the beta-sheet breaker peptides known today. Further molecular modeling simulations suggested that the hybrid ligands were incorporated into the β-sheet structure of Aβ aggregates, indicating that the hybrid ligands may bind to Aβ but are unable to inhibit further aggregation. Optimization of the hybrid ligands by reducing hydrogen bond interactions of the ligand with following Aβ proteins might result in ligands, with improved binding to one Aβ protein, that could potentially disrupt further β-sheet formation. This in turn may reduce toxicity of Aβ. |
| Databáze: | OpenAIRE |
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