Designed α-sheet peptides inhibit amyloid formation by targeting toxic oligomers
Gene Hopping,
Jackson Kellock,
Ravi Pratap Barnwal,
Peter Law,
James Bryers,
Gabriele Varani,
Byron Caughey,
Valerie Daggett
Affiliations
Gene Hopping
Department of Bioengineering, University of Washington, Seattle, United States
Jackson Kellock
Department of Bioengineering, University of Washington, Seattle, United States
Ravi Pratap Barnwal
Department of Chemistry, University of Washington, Seattle, United States
Peter Law
Department of Bioengineering, University of Washington, Seattle, United States
James Bryers
Department of Bioengineering, University of Washington, Seattle, United States
Gabriele Varani
Department of Chemistry, University of Washington, Seattle, United States
Byron Caughey
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, United States
Valerie Daggett
Department of Bioengineering, University of Washington, Seattle, United States
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.
