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

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)


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-ThiNva; 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 languageEnglish
Pages (from-to)5626-5640
Number of pages15
JournalBioorganic and Medicinal Chemistry
Issue number17
Publication statusPublished - 2015 Jun 27


  • 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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