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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‐]
Author(s) -
Arai Tadamasa,
Araya Takushi,
Sasaki Daisuke,
Taniguchi Atsuhiko,
Sato Takeshi,
Sohma Youhei,
Kanai Motomu
Publication year - 2014
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201405109
Subject(s) - pharmacophore , chemistry , rational design , small molecule , structural motif , stereochemistry , amide , peptide , amyloid (mycology) , molecule , drug discovery , combinatorial chemistry , biochemistry , organic chemistry , biology , inorganic chemistry , genetics
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.