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

What Can the Kinetics of Amyloid Fibril Formation Tell about Off-pathway Aggregation?

“…In cases of extensive OPA, increasing the protein concentration may even prolong the duration of the lag phase and decrease the amyloid aggregation rate. This angle of approach is, to our knowledge, totally original because the main focus has been on the detection and morphological/ toxicological characterization of the amorphous precipitates (4,7,8,9,14). The new possibility of estimating the relative amounts of off-pathway and amyloid aggregates accentuates the need for cataloguing the deleterious species in each disease.…”

Inhibition of protein aggregation and amyloid formation by small molecules

“…Using molecular dynamics (MD) simulations, a1 and a3 of 23 and 21 amino acids, with alternating D-amino acids and L-amino acids, were designed to be a linear hairpin having high a-sheet and a cyclic amide backbone, respectively. Both peptides reduce Ab1-42 and TTR aggregation and toxicity at molar ratio of at least 10:1, but crossing BBB is highly unlikely [28]. Pande [29] and Arai [30 ] also designed two compounds.…”

Biophysical insight into the anti-amyloidogenic behavior of taurine

“…MTT in the presence of viable cells reduce to form blue formazan crystals, toxicity leads to inhibition of formazon production [28]. For the MTT reduction assays, sample solutions of HSA with 250 and 750 M concentrations of taurine were added to the PC12/ SH-SY5Y cells in the 96-well plates.…”