Figure 1.

Top, outline of workflow used to design and test inhibitors of tau seeding. Figure citations are of figures in this paper, and lozenges are colored to correspond to A–E in this figure. A, ZipperDB (20) prediction of the aggregation-driving peptide segments in tau identifies segments VQIINK and VQIVYK. Sequences with scores exceeding an empirical threshold of −23 kcal/mol on the vertical axis (colored red) report hexapeptide segments with energetically favorable steric zipper scores. B, nanocrystals of the SVQIVY peptide segment predicted from the ZipperDB plot in A to have greater steric zipper–forming propensity compared with the parent segment, VQIVYK. C, electron diffraction collected by micro-ED from representative SVQIVY nanocrystals shown in B. D, model of a fibril-capping inhibitor (magenta) designed to block elongation by binding to the tip of a fibril (gray). The example shown is of a VQIINK capping inhibitor, WMINK, designed to inhibit aggregation from three interfaces formed by different polymorphs of the VQIINK steric zipper, labeled interface A, B, and C (19). E, seeding inhibition assay, carried out by transfecting tau biosensor cells (32) with tau fibrils (recombinant or brain-derived, as indicated) that were pretreated with capping inhibitor.