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摘要
The aggregation of peptides/proteins is intimately related to a number of human diseases. More than 20 have been identified which aggregate into fibrils containing extensive beta-sheet structures, and species generated in the aggregation processes (i.e., oligomers and fibrils) contribute to disease development. Amyloid-beta peptide (designated A beta), related to Alzheimer's disease (AD), is the representative example. The intensive aggregation property of A beta also leads to difficulty in its synthesis. To improve the synthetic problem, we developed an O-acyl isopeptide of A beta 1-42, in which the N-acyl linkage (amide bond) of Ser(26) was replaced with an O-acyl linkage (ester bond) at the side chain. The O-acyl isopeptide demonstrated markedly higher water-solubility than that of A beta 1-42, while it quickly converted to intact monomer A beta 1-42 via an O-to-N acyl rearrangement under physiological conditions. Inhibition of the pathogenic aggregation of A beta 1-42 might be a therapeutic strategy for curing AD. We succeeded in the rational design and identification of a small molecule aggregation inhibitor based on a pharmacophore motif obtained from cyclo[-Lys-Leu-Val-Phe-Phe-]. Moreover, the inhibition of A beta aggregation was achieved via oxygenation (i.e., incorporation of oxygen atoms to A beta) using an artificial catalyst. We identified a selective, cell-compatible photo-oxygenation catalyst of A beta, a flavin catalyst attached to an A beta-binding peptide, which markedly decreased the aggregation potency and neurotoxicity of A beta.
- 出版日期2016-1
