Modulating amyloid-β aggregation: The effects of peptoid side chain placement and chirality.

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.

journal_name

Bioorg Med Chem

authors

Turner JP,Chastain SE,Park D,Moss MA,Servoss SL

doi

10.1016/j.bmc.2016.10.007

subject

Has Abstract

pub_date

2017-01-01 00:00:00

pages

20-26

issue

1

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(16)30921-X

journal_volume

25

pub_type

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