title: Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity.
abstract: 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 fibres. 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 the 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 the amyloid-β peptide 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.
authors.affiliation: Department of Chemistry, University of California, Irvine, California 92697-2025, USA.
authors.forename: Pin-Nan
authors.initials: PN
authors.lastname: Cheng
authors.forename: Cong
authors.initials: C
authors.lastname: Liu
authors.forename: Minglei
authors.initials: M
authors.lastname: Zhao
authors.forename: David
authors.initials: D
authors.lastname: Eisenberg
authors.forename: James S
authors.initials: JS
authors.lastname: Nowick
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D016716:PC12 Cells; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects*; D017433:Protein Structure, Secondary; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D047028:Macrocyclic Compounds; D057786:Peptidomimetics