Pathological peptide folding in Alzheimer's disease and other conformational disorders.
Main neuropathological hallmarks of Alzheimer's disease (AD) and other neurodegenerative disorders are the deposition of neurofibrillary tangles consisting of abnormally phosphorylated protein tau and of senile plaques largely containing insoluble beta-amyloid peptides (A beta), containing up to 43 amino acid residues derived from the beta-amyloid precursor protein. Such A beta-sheets become visible by using suitable histochemical methods. Molecular simulation showed that the central, alpha-helical, lipophilic, antigenic folding domain of the A beta-peptide loop is a promising molecular target of beta-sheet breakers that thus prevent the polymerization of A beta into aggregates. It seems that di- and tetramers of A beta-peptides have a beta-barrel- like structure. In the present review, an optimized neural network analysis was applied to recognize possible structure-activity relationships of peptidomimetic beta-sheet breakers. The anti-aggregatory potency of beta-sheet breakers largely depends upon their total, electrostatic, and hydration energy as derived from their geometry-optimized conformations using the hybrid Gasteiger-molecular mechanics approach. Moreover, we also summarize peptide misfolding in several disorders with distinct clinical symptoms, including prion diseases and a broad variety of systemic amyloidoses, as the common pathogenic step driving these disorders. In particular, conversion of nontoxic alpha-helix/random-coils to beta-sheet conformation was recognized as being critical in producing highly pathogenic peptide assemblies. Whereas conventional pharmacotherapy of AD is mainly focused on restoring cholinergic activity and diminishing inflammatory responses as a consequence of amyloid accumulation, we here survey potential approaches aimed at preventing or reserving the transition of neurotoxic peptide species from alpha-helical/random coil to beta-sheet conformation and thus abrogating their effects in a broad variety of disorders.
D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000187:drug effects; D000686:Amyloidosis / Q000188:drug therapy / Q000209:etiology*; D006801:Humans; D008024:Ligands; D011487:Protein Conformation / Q000187:drug effects; D017510:Protein Folding; D021281:Quantitative Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D008024:Ligands