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139757 - Peptidomimetic modulators of BACE - Final author version.pdf (623.01 kB)

Peptidomimetic modulators of BACE1

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posted on 2023-05-20, 15:47 authored by Juliano, JP, David SmallDavid Small, Aguilar, M-I
The β-site APP Cleaving enzyme 1 (BACE1) is a membrane-associated aspartyl protease which mediates the production of amyloid-β (Aβ), a major component of amyloid plaques in the Alzheimer's disease brain. We have synthesised and characterised a series of peptidomimetic analogues of BACE substrates that incorporate two distinct stabilising structures. To demonstrate the potential activity of these compounds, a variety of assaying strategies were used to investigate cleavage susceptibility and inhibition potency under competitive and non-competitive conditions. β-Amino acids and scissile site N-methylation were incorporated into peptide substrate templates as transition state isostere (TSI) substitutes by positional scanning to generate series of non-TSI β-peptidomimetics. The amino acid sequences flanking the β-cleavage site within APP carrying the Swedish double mutation (APPSW), Neuregulin, the synthetic hydroxyethylene-based TSI peptide inhibitor OM99-2, and the high affinity peptide sequence SEISYEVEFR, served as the four substrate templates from which over 60 peptides were designed and synthesised by solid phase peptide synthesis. A quenched fluorescent substrate BACE1 assay in conjunction with liquid chromatography-mass spectrometry (LC-MS) analysis was established to investigate cleavage susceptibility and inhibition potency under competitive and non-competitive conditions. It was determined that β-amino acids substituted at the P1 scissile site position within known peptide substrates were resistant to proteolysis, and particular substitutions induced a concentration-dependent stimulation of BACE1, indicating a possible modulatory role of native BACE1 substrates.

History

Publication title

Australian Journal of Chemistry

Volume

73

Issue

4

Pagination

366-376

ISSN

0004-9425

Department/School

Menzies Institute for Medical Research

Publisher

CSIRO Publishing

Place of publication

150 Oxford St, Po Box 1139, Collingwood, Australia, Victoria, 3066

Rights statement

Copyright CSIRO 2020

Repository Status

  • Open

Socio-economic Objectives

Clinical health not elsewhere classified

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