Amyloid β-Sheet Mimics that Antagonize Amyloid Aggregation and Reduce Amyloid Toxicity

The amyloid protein aggregation associated with diseases such as Alzheimer’s, Parkinson’s, and type II diabetes (among many others), features a bewildering variety of β-sheet-rich structures in transition from native proteins to ordered oligomers and fibers. The variation in the amino acid sequences of the β-structures presents a challenge to developing a model system of β-sheets for the study of various amyloid aggregates. Here we introduce a family of robust β-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid β-sheet mimics (ABSMs) to antagonize aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from Aβ associated with Alzheimer’s disease, β(2)-microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson’s disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles.