Rational Design and Identification of a Non-Peptidic Aggregation Inhibitor of Amyloid-β Based on a Pharmacophore Motif Obtained from cyclo[-Lys-Leu-Val-Phe-Phe-]

Inhibition of pathogenic protein aggregation may be an important and straightforward therapeutic strategy for curing amyloid diseases. Small-molecule aggregation inhibitors of Alzheimer's amyloid-beta (A beta) are extremely scarce, however, and are mainly restricted to dye- and polyphenol-type compounds that lack drug-likeness. Based on the structureactivity relationship of cyclic 416-20 (cyclo-/KLVFFJ), we identified unique pharmacophore motifs comprising sidechains of Leu(2), Var, Phe(4), and Phe(5) residues without involvement of the backbone amide bonds to inhibit A beta aggregation. This finding allowed us to design non-peptidic, small-molecule aggregation inhibitors that possess potent activity. These molecules are the first successful non-peptidic, small-molecule aggregation inhibitors of amyloids based on rational molecular design.