title: Hydrophobicity and conformational change as mechanistic determinants for nonspecific modulators of amyloid β self-assembly.
abstract: The link between many neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, and the aberrant folding and aggregation of proteins has prompted a comprehensive search for small organic molecules that have the potential to inhibit such processes. Although many compounds have been reported to affect the formation of amyloid fibrils and/or other types of protein aggregates, the mechanisms by which they act are not well understood. A large number of compounds appear to act in a nonspecific way affecting several different amyloidogenic proteins. We describe here a detailed study of the mechanism of action of one representative compound, lacmoid, in the context of the inhibition of the aggregation of the amyloid β-peptide (Aβ) associated with Alzheimer's disease. We show that lacmoid binds Aβ(1-40) in a surfactant-like manner and counteracts the formation of all types of Aβ(1-40) and Aβ(1-42) aggregates. On the basis of these and previous findings, we are able to rationalize the molecular mechanisms of action of nonspecific modulators of protein self-assembly in terms of hydrophobic attraction and the conformational preferences of the polypeptide.
authors: Department of Biochemistry and Biophysics, Stockholm University, Svante Arrhenius v. 16, SE-106 91 Stockholm, Sweden.
authors: Axel
authors: A
authors: Abelein
authors: Benedetta
authors: B
authors: Bolognesi
authors: Christopher M
authors: CM
authors: Dobson
authors: Astrid
authors: A
authors: Gräslund
authors: Christofer
authors: C
authors: Lendel
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry*; D001667:Binding, Competitive; D002942:Circular Dichroism; D003224:Congo Red / Q000737:chemistry; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D049329:Nanostructures / Q000737:chemistry*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010078:Oxazines / Q000737:chemistry*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D012542:Scattering, Radiation; D054852:Small Molecule Libraries / Q000737:chemistry; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D010078:Oxazines; D010446:Peptide Fragments; D054852:Small Molecule Libraries; D013501:Surface-Active Agents; C078592:amyloid beta-protein (1-40); C570487:lacmoid; D003224:Congo Red