Modulating amyloid-β aggregation: The effects of peptoid side chain placement and chirality. Issue 1 (1st January 2017)

• Record Type: Journal Article
• Authors: Turner, J. Phillip; Chastain, Shelby E.; Park, Dongwon; Moss, Melissa A.; Servoss, Shannon L.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 1(2017)
• Page Start: 20
• Page End: 26
• Publication Date: 2017-01-01
• Subjects: AD Alzheimer's disease -- Aβ amyloid-β protein -- Aβ40 amyloid-β 1–40 -- Aβ42 amyloid-β 1–42 -- HD Huntington's disease -- ThT thioflavin T -- DMF dimethylformamide -- TFA trifluoroacetic acid -- HPLC high performance liquid chromatography -- TEM transmission electron microscopy -- DMSO dimethyl sulfoxide; Alzheimer's disease -- Peptoid -- Amyloid-beta -- KLVFF -- Inhibitor -- Protein aggregation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.10.007
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Alzheimer's disease (AD) is characterized by the buildup of insoluble aggregated amyloid-β protein (Aβ) into plaques that accumulate between the neural cells in the brain. AD is the sixth leading cause of death in the United States and is the only cause of death among the top ten that cannot currently be treated or cured (Alzheimer's Association, 2011; Selkoe, 1996). Researchers have focused on developing small molecules and peptides to prevent Aβ aggregation; however, while some compounds appear promising in vitro, the research has not resulted in a viable therapeutic treatment. We previously reported a peptoid-based mimic (JPT1) of the peptide KLVFF (residues 16–20 of Aβ) that modulates Aβ40 aggregation, specifically reducing the total number of fibrillar, β-sheet structured aggregates formed. In this study, we investigate two new variants of JPT1 that probe the importance of aromatic side chain placement (JPT1s) and side chain chirality (JPT1a). Both JPT1s and JPT1a modulate Aβ40 aggregation by reducing total β-sheet aggregates. However, JPT1a also has a pronounced effect on the morphology of fibrillar Aβ40 aggregates. These results suggest that Aβ40 aggregation may follow a different pathway in the presence of peptoids with different secondary structures. A better understanding of the interactions between peptoids and Aβ will allow for improved design of AD treatments.