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‐] |
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| Authors: | Tadamasa Arai Takushi Araya Dr Daisuke Sasaki Dr Atsuhiko Taniguchi Dr Takeshi Sato Dr Youhei Sohma Prof Motomu Kanai |
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| Affiliation: | 1. Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo‐ku, Tokyo 113‐0033 (Japan);2. ERATO (Japan) Science and Technology Agency (JST), Kanai Life Science Catalysis Project, Tokyo 113‐0033 (Japan);3. Institute for Protein Research, Osaka University, Suita, Osaka 565‐0871 (Japan) |
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| 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 Leu2, Val3, Phe4, and Phe5 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. |
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| Keywords: | aggregation Alzheimer’ s disease amyloid drug design inhibitors |
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