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Designed Glycopeptidomimetics Disrupt Protein-Protein Interactions Mediating Amyloid β-Peptide Aggregation and Restore Neuroblastoma Cell Viability. | LitMetric

AI Article Synopsis

  • The study investigates how new sugar-based peptidomimetics can inhibit the early aggregation and fibrillization of the neurotoxic amyloid beta 1-42 (Aβ1-42) peptide, which is linked to Alzheimer's disease.
  • Using advanced techniques like capillary electrophoresis and nuclear magnetic resonance, researchers found that these molecules effectively interact with toxic oligomers to maintain safer monomer forms and prevent toxic accumulation.
  • The most effective compound features a combination of hydrophobic properties, hydrogen bonding capabilities, ammonium groups, and elements that disrupt β-sheet formation, indicating potential directions for designing future Alzheimer's drug candidates.

Article Abstract

How anti-Alzheimer's drug candidates that reduce amyloid 1-42 peptide fibrillization interact with the most neurotoxic species is far from being understood. We report herein the capacity of sugar-based peptidomimetics to inhibit both Aβ1-42 early oligomerization and fibrillization. A wide range of bio- and physicochemical techniques, such as a new capillary electrophoresis method, nuclear magnetic resonance, and surface plasmon resonance, were used to identify how these new molecules can delay the aggregation of Aβ1-42. We demonstrate that these molecules interact with soluble oligomers in order to maintain the presence of nontoxic monomers and to prevent fibrillization. These compounds totally suppress the toxicity of Aβ1-42 toward SH-SY5Y neuroblastoma cells, even at substoichiometric concentrations. Furthermore, demonstration that the best molecule combines hydrophobic moieties, hydrogen bond donors and acceptors, ammonium groups, and a hydrophilic β-sheet breaker element provides valuable insight for the future structure-based design of inhibitors of Aβ1-42 aggregation.

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Source
http://dx.doi.org/10.1021/acs.jmedchem.5b01629DOI Listing

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