Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors

Yasunao Hattori; Kazuya Kobayashi; Ayaka Deguchi; Yukie Nohara; Tomomi Akiyama; Kenta Teruya; Akira Sanjoh; Atsushi Nakagawa; Eiki Yamashita; Kenichi Akaji

doi:10.1016/j.bmc.2015.07.023

Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors

Yasunao Hattori, Kazuya Kobayashi, Ayaka Deguchi, Yukie Nohara, Tomomi Akiyama, Kenta Teruya, Akira Sanjoh, Atsushi Nakagawa, Eiki Yamashita, Kenichi Akaji

MED - United Centers for Advanced Research and Translational Medicine (ART)

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	5626-5640
Number of pages	15
Journal	Bioorganic and Medicinal Chemistry
Volume	23
Issue number	17
DOIs	https://doi.org/10.1016/j.bmc.2015.07.023
Publication status	Published - 2015 Jun 27

Keywords

BACE 1
Hydroxyethylamine
Hydroxymethylcarbonyl
Inhibitor
Transition state mimic

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmc.2015.07.023

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@article{13d7629226094023ba2c7d31467000e4,

title = "Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors",

abstract = "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.",

keywords = "BACE 1, Hydroxyethylamine, Hydroxymethylcarbonyl, Inhibitor, Transition state mimic",

author = "Yasunao Hattori and Kazuya Kobayashi and Ayaka Deguchi and Yukie Nohara and Tomomi Akiyama and Kenta Teruya and Akira Sanjoh and Atsushi Nakagawa and Eiki Yamashita and Kenichi Akaji",

note = "Funding Information: The authors are grateful to Dr. Taeko Kakizawa for her initial contributions in the preliminary experiments on solid-phase syntheses using commercially available HMC derivatives. The authors are also grateful to Dr. Taku Yoshiya for his useful suggestions regarding the syntheses of HMC derivatives by reduction of the α-keto acid derivatives. The authors are also grateful to Saki Goto, Mami Okabe, Natsumi Sato, Kanami Ueno, and Miki Ito for their contribution regarding the syntheses of inhibitors. This work was supported, in part, by a Grant-in-aid for Scientific Research 25460160 to K.A. from the Ministry of Education, Culture, Sports, Science, and Technology , Japan. This research is (partially) supported by the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics and Structural Life Science) from the Ministry of Education, Culture, Sports, Science, and Technology , Japan. Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd. All rights reserved.",

year = "2015",

month = jun,

day = "27",

doi = "10.1016/j.bmc.2015.07.023",

language = "English",

volume = "23",

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journal = "Bioorganic and Medicinal Chemistry",

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T1 - Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors

AU - Hattori, Yasunao

AU - Kobayashi, Kazuya

AU - Deguchi, Ayaka

AU - Nohara, Yukie

AU - Akiyama, Tomomi

AU - Teruya, Kenta

AU - Sanjoh, Akira

AU - Nakagawa, Atsushi

AU - Yamashita, Eiki

AU - Akaji, Kenichi

N1 - Funding Information: The authors are grateful to Dr. Taeko Kakizawa for her initial contributions in the preliminary experiments on solid-phase syntheses using commercially available HMC derivatives. The authors are also grateful to Dr. Taku Yoshiya for his useful suggestions regarding the syntheses of HMC derivatives by reduction of the α-keto acid derivatives. The authors are also grateful to Saki Goto, Mami Okabe, Natsumi Sato, Kanami Ueno, and Miki Ito for their contribution regarding the syntheses of inhibitors. This work was supported, in part, by a Grant-in-aid for Scientific Research 25460160 to K.A. from the Ministry of Education, Culture, Sports, Science, and Technology , Japan. This research is (partially) supported by the Platform Project for Supporting in Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics and Structural Life Science) from the Ministry of Education, Culture, Sports, Science, and Technology , Japan. Publisher Copyright: © 2015 Elsevier Ltd. All rights reserved.

PY - 2015/6/27

Y1 - 2015/6/27

N2 - 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.

AB - 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.

KW - BACE 1

KW - Hydroxyethylamine

KW - Hydroxymethylcarbonyl

KW - Inhibitor

KW - Transition state mimic

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DO - 10.1016/j.bmc.2015.07.023

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AN - SCOPUS:84946496542

SN - 0968-0896

VL - 23

SP - 5626

EP - 5640

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 17

ER -

Evaluation of transition-state mimics in a superior BACE1 cleavage sequence as peptide-mimetic BACE1 inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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