title: BACE1 Inhibitor Peptides: Can an Infinitely Small k cat Value Turn the Substrate of an Enzyme into Its Inhibitor?
abstract: Recently, we reported substrate-based pentapeptidic β-secretase (BACE1) inhibitors with a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent BACE1 inhibitory activity in enzyme and cell assays, with KMI-429 showing in vivo inhibition of Aβ production. We also designed and synthesized nonpeptidic and small-sized BACE1 inhibitors using "in-silico conformational structure-based design". By studying the structure-activity relationship of these inhibitors, we found that the σ-π interaction of an inhibitor with the BACE1-Arg235 side chain played a key role in the inhibition of BACE1. We speculated that a peptide capable of binding to the BACE1-Arg235 side chain via the σ-π interaction might exhibit BACE1 inhibitory activity. Hence, we designed and synthesized a series of peptides that were modified at the P2 position and found that some of these peptides exhibited a potent BACE1 inhibitory activity despite their structural similarity to the BACE1 substrate.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kobe Gakuin University , Minatojima, Chuo-ku, Kobe 650-8586, Japan ; Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University , Yamashina-ku, Kyoto 607-8412, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hamada
authors.affiliation: Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo , Meguro-ku, Tokyo 153-8902, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ishiura
authors.affiliation: Faculty of Pharmaceutical Sciences, Kobe Gakuin University , Minatojima, Chuo-ku, Kobe 650-8586, Japan ; Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University , Yamashina-ku, Kyoto 607-8412, Japan ; Laboratory of Peptide Science, Nagahama Institute of Bio-Science and Technology , Tamura-cho, Nagahama 526-0829, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kiso
keywords: Alzheimer’s disease; BACE1; BACE1 inhibitor; inhibitor peptide; substrate; β-secretase