Small molecule ligands rationally designed to complement β-sheet hydrogen-bond patterns present in fibrils, but that halt continuation of the β-sheet, e.g., aminopyrazole derivatives, have been known for some time (1,2). These β-sheet-complementing substances, however, lack specificity for fibrils built of a certain protein or peptide.
Sievers and colleagues report a very elegant study on the rational, 3-dimensional structure-based design of small peptide ligands that specifically bind to their target molecules in fibrillar conformation. Their decisive advantage over the aforementioned β-sheet-complementing substances is specificity. Sievers et al. clearly show that they arrive at peptides that bind specifically and show interesting activities in vitro.
The researchers combine the advantages of β-sheet-complementing compounds with those of substances that can specifically bind a certain amyloidogenic peptide or protein—more or less irrespective of its conformation.
Recently, we described a distantly similar approach when we covalently linked a classical...