Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors.
A superior substrate sequence for BACE1 containing transition-state mimics at the scissile site was evaluated as a protease inhibitor. Hydroxymethylcarbonyl (HMC) and hydroxyethylamine (HEA) isosteres were selected as the transition state mimics, and incorporated into the scissile site of the superior sequence covering the P4 to P1' sites (Glu-Ile-Thi-Thi(*)Nva; (*)denotes the cleavage site). Isosteres having different absolute configurations of the hydroxyl group were synthesized separately, and the effect of the configuration was evaluated. Configuration of the hydroxyl group of each isostere showed a marked effect on the inhibitory activity; anti-configuration to the scissile site substituent had potent inhibitory activity in an HMC-type inhibitor, whereas anti-configuration of HEA-type inhibitors showed no inhibitory activity. Structural evaluations based on X-ray crystallographic analyses of recombinant BACE1 in complex with each inhibitor provided insights into the protein-ligand interactions, especially at the prime sites.
Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Yasunao
Y
Hattori
Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Kazuya
K
Kobayashi
Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Ayaka
A
Deguchi
Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Yukie
Y
Nohara
Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Tomomi
T
Akiyama
Department of Neurochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
Kenta
K
Teruya
R&D Center, Protein Wave Co., Nara 631-0006, Japan.
Akira
A
Sanjoh
Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
Atsushi
A
Nakagawa
Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan.
Eiki
E
Yamashita
Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan. Electronic address: akaji@mb.kyoto-phu.ac.jp.
Kenichi
K
Akaji
D000544:Alzheimer Disease / Q000235:genetics*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D001665:Binding Sites; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*
D010455:Peptides; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
BACE 1; Hydroxyethylamine; Hydroxymethylcarbonyl; Inhibitor; Transition state mimic