Figure 1. Scheme for the design and characterization of peptide inhibitors of amyloid fibrillation.

Tau constructs form fibers in vitro (top left)²⁴. The VQIVYK segment in isolation forms fibers and microcrystals (bottom left). The atomic structure of the fiber-like VQIVYK segment reveals a characteristic steric zipper motif¹⁵, comprising a pair of interacting β-sheets running along the fiber axis (grey arrow), in purple and grey (bottom right). We designed a D-amino acid peptide to bind to the end of the steric zipper template and prevent fiber elongation (middle right). The D-peptide, in red, is designed to satisfy hydrogen bonds and make favorable apolar interactions with the molecule below, while preventing the addition of other molecules above and on the opposite β-sheet. As shown in vitro, the designed D-peptide prevents the formation of fibers when incubated with tau K19 (upper right). Scale bars are 100 μm and 200 nm on the microcrystal image and electron micrographs, respectively.