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- W2911768251 abstract "Amyloid proteins misfold from their natural, functional conformations and aggregate into insoluble, highly structured beta-sheet-rich fibers. These proteins are associated with several diseases, including Huntington's disease, Parkinson's disease, type II diabetes (T2DM), and Alzheimer's disease (AD). T2DM and AD share common amyloid pathologies, wherein islet amyloid polypeptide (IAPP) and amyloid beta (Aβ), respectively, form toxic intermediate oligomers, some of which sample a-helical conformations, during their transition to fibrils. Our approach takes advantage of these intermediates to target these peptides in a conformation- and chemical property-specific manner. We designed a library of small molecule a-helical mimetics, specifically oligoquinolines and oligopyrrolamides, that present surface functionalities in a well-defined order to mimic the residues at position i, i +3/+4, and i+7, of the helical surface. The rationale is to stabilize these peptides, thereby preventing their oligomerization and fibrillation, by matching the scaffold side-chains to complementary residues in the helical peptide domain. Previously we showed that the oligoquinoline 5, with alternating negatively-charged and hydrophobic side-chains, is a potent antagonist of Aβ aggregation. Here we have investigated whether 5 maintains inhibitory potential in the presence of zinc, a metal ion that has been reported to associate with Aβ and affect its conformation, aggregation, and toxicity. Other work on oligopyrrolamides demonstrated their antagonistic effects on IAPP aggregation and toxicity. Due to the similarity between IAPP and Aβ, oligopyrrolamides were also screened against Aβ. Our results show that ADH-120 is a potent inhibitor of Aβ aggregation but only in the absence of zinc. Biophysical assays were used to compare the activity of 5 and ADH-120 against Aβ, both in the presence and absence of zinc, as well as to determine trends in Aβ inhibition within the oligopyrrolamide library to elucidate structure-activity relationship of the scaffold." @default.
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- W2911768251 date "2019-02-01" @default.
- W2911768251 modified "2023-09-30" @default.
- W2911768251 title "Inhibition of Zinc-Mediated Amyloid Beta Aggregation and Cytotoxicity by Alpha Helix Mimetics" @default.
- W2911768251 doi "https://doi.org/10.1016/j.bpj.2018.11.2590" @default.
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