A rational design to create hybrid beta-sheet breaker peptides to inhibit aggregation and toxicity of amyloid-beta

Alzheimer's disease is characterized by deposits of the amyloid beta protein (A beta) in the form of senile plaques and cerebral amyloid angiopathy. Deposition of A beta into these pathological lesions is directed by step-wise aggregation of A beta into oligomers, protofibrils and mature fibrils. Currently, all therapies are purely symptom-relieving, and an actual treatment or prevention of A beta is still lacking. Since aggregated forms of A beta are particularly neurotoxic, interference with the process of A beta aggregation is a long-envisioned target for therapy. Based on the knowledge that both sulfated (macro)molecules and small synthetic peptides interfere with A beta aggregation, we developed hybrid ligands to target A beta 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 A beta(42). The hybrid ligands that we designed, synthesized and evaluated were found to be non-toxic to cells but displayed negligible inhibition of A beta fibrillization and A beta-mediated cytotoxicity compared to the beta-sheet breaker peptides known today. Further molecular modeling simulations suggested that the hybrid ligands were incorporated into the beta-sheet structure of A beta aggregates, indicating that the hybrid ligands may bind to A beta but are unable to inhibit further aggregation. Optimization of the hybrid ligands by reducing hydrogen bond interactions of the ligand with following A beta proteins might result in ligands, with improved binding to one A beta protein, that could potentially disrupt further beta-sheet formation. This in turn may reduce toxicity of A beta.