title: 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-].
abstract: 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-β (Aβ) are extremely scarce, however, and are mainly restricted to dye- and polyphenol-type compounds that lack drug-likeness. Based on the structure-activity relationship of cyclic Aβ16-20 (cyclo-[KLVFF]), we identified unique pharmacophore motifs comprising side-chains of Leu(2), Val(3), Phe(4), and Phe(5) residues without involvement of the backbone amide bonds to inhibit Aβ 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033 (Japan); ERATO (Japan) Science and Technology Agency (JST), Kanai Life Science Catalysis Project, Tokyo 113-0033 (Japan).
authors.forename: Tadamasa
authors.initials: T
authors.lastname: Arai
authors.forename: Takushi
authors.initials: T
authors.lastname: Araya
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sasaki
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Taniguchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sato
authors.forename: Youhei
authors.initials: Y
authors.lastname: Sohma
authors.forename: Motomu
authors.initials: M
authors.lastname: Kanai
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D015195:Drug Design; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D010456:Peptides, Cyclic
keywords: Alzheimer’s disease; aggregation; amyloid; drug design; inhibitors