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

作者：Turner J Phillip; Chastain Shelby E; Park Dongwon; Moss Melissa A; Servoss Shannon L^*

来源：Bioorganic & Medicinal Chemistry, 2017, 25(1): 20-26.

DOI：10.1016/j.bmc.2016.10.007

• Alzheimer's disease
• Peptoid
• Amyloid-beta
• KLVFF
• Inhibitor
• Protein aggregation

Alzheimer's disease (AD) is characterized by the buildup of insoluble aggregated amyloid-beta protein (A beta) 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 A beta 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 A beta) that modulates A beta 40 aggregation, specifically reducing the total number of fibrillar, b-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 A beta 40 aggregation by reducing total b-sheet aggregates. However, JPT1a also has a pronounced effect on the morphology of fibrillar A beta 40 aggregates. These results suggest that A beta 40 aggregation may follow a different pathway in the presence of peptoids with different secondary structures. A better understanding of the interactions between peptoids and A beta will allow for improved design of AD treatments.

• 出版日期2017-1-1