title: Peptides Composed of Alternating L- and D-Amino Acids Inhibit Amyloidogenesis in Three Distinct Amyloid Systems Independent of Sequence.
abstract: There is now substantial evidence that soluble oligomers are primary toxic agents in amyloid diseases. The development of an antibody recognizing the toxic soluble oligomeric forms of different and unrelated amyloid species suggests a common conformational intermediate during amyloidogenesis. We previously observed a common occurrence of a novel secondary structure element, which we call α-sheet, in molecular dynamics (MD) simulations of various amyloidogenic proteins, and we hypothesized that the toxic conformer is composed of α-sheet structure. As such, α-sheet may represent a conformational signature of the misfolded intermediates of amyloidogenesis and a potential unique binding target for peptide inhibitors. Recently, we reported the design and characterization of a novel hairpin peptide (α1 or AP90) that adopts stable α-sheet structure and inhibits the aggregation of the β-Amyloid Peptide Aβ42 and transthyretin. AP90 is a 23-residue hairpin peptide featuring alternating D- and L-amino acids with favorable conformational propensities for α-sheet formation, and a designed turn. For this study, we reverse engineered AP90 to identify which of its design features is most responsible for conferring α-sheet stability and inhibitory activity. We present experimental characterization (CD and FTIR) of seven peptides designed to accomplish this. In addition, we measured their ability to inhibit aggregation in three unrelated amyloid species: Aβ42, transthyretin, and human islet amylin polypeptide. We found that a hairpin peptide featuring alternating L- and D-amino acids, independent of sequence, is sufficient for conferring α-sheet structure and inhibition of aggregation. Additionally, we show a correlation between α-sheet structural stability and inhibitory activity.
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98105-5013, USA.
authors.forename: Jackson
authors.initials: J
authors.lastname: Kellock
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98105-5013, USA.
authors.forename: Gene
authors.initials: G
authors.lastname: Hopping
authors.affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840-2932, USA.
authors.forename: Byron
authors.initials: B
authors.lastname: Caughey
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA 98105-5013, USA. Electronic address: daggett@uw.edu.
authors.forename: Valerie
authors.initials: V
authors.lastname: Daggett
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism*; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D058227:Amyloidogenic Proteins / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D011228:Prealbumin / Q000378:metabolism; D066329:Protein Aggregates / Q000502:physiology; D055503:Protein Multimerization / Q000502:physiology; D017433:Protein Structure, Secondary
chemical_list: D000596:Amino Acids; D000682:Amyloid; D016229:Amyloid beta-Peptides; D058227:Amyloidogenic Proteins; D058228:Islet Amyloid Polypeptide; D011228:Prealbumin; D066329:Protein Aggregates
keywords: amyloid; beta amyloid; inhibitor; toxic oligomer; α-sheet