title: Designed α-sheet peptides inhibit amyloid formation by targeting toxic oligomers.
abstract: Previous studies suggest that the toxic soluble-oligomeric form of different amyloid proteins share a common backbone conformation, but the amorphous nature of this oligomer prevents its structural characterization by experiment. Based on molecular dynamics simulations we proposed that toxic intermediates of different amyloid proteins adopt a common, nonstandard secondary structure, called α-sheet. Here we report the experimental characterization of peptides designed to be complementary to the α-sheet conformation observed in the simulations. We demonstrate inhibition of aggregation in two different amyloid systems, β-amyloid peptide (Aβ) and transthyretin, by these designed α-sheet peptides. When immobilized the α-sheet designs preferentially bind species from solutions enriched in the toxic conformer compared with non-aggregated, nontoxic species or mature fibrils. The designs display characteristic spectroscopic signatures distinguishing them from conventional secondary structures, supporting α-sheet as a structure involved in the toxic oligomer stage of amyloid formation and paving the way for novel therapeutics and diagnostics.DOI: http://dx.doi.org/10.7554/eLife.01681.001.
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, United States.
authors.forename: Gene
authors.initials: G
authors.lastname: Hopping
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, United States.
authors.forename: Jackson
authors.initials: J
authors.lastname: Kellock
authors.affiliation: Department of Chemistry, University of Washington, Seattle, United States.
authors.forename: Ravi Pratap
authors.initials: RP
authors.lastname: Barnwal
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Law
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, United States.
authors.forename: James
authors.initials: J
authors.lastname: Bryers
authors.affiliation: Department of Chemistry, University of Washington, Seattle, United States.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Varani
authors.affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, United States.
authors.forename: Byron
authors.initials: B
authors.lastname: Caughey
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, United States daggett@u.washington.edu.
authors.forename: Valerie
authors.initials: V
authors.lastname: Daggett
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011228:Prealbumin / Q000378:metabolism*; D066329:Protein Aggregates; D011487:Protein Conformation; D055503:Protein Multimerization / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D010455:Peptides; D011228:Prealbumin; D066329:Protein Aggregates
keywords: alpha-sheet; amyloidosis; computational design; toxic oligomer