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RESEARCH ARTICLE
Contents Vol 73(4)

Peptidomimetic Modulators of BACE1

John Paul Juliano A , David H. Small B and Marie-Isabel Aguilar https://orcid.org/0000-0002-0234-4064 A C
+ Author Affiliations
- Author Affiliations

A Department of Biochemistry and Molecular Biology, Monash University, Clayton, Vic. 3800, Australia.

B Menzies Research Institute, University of Tasmania, Hobart, Tas. 7005, Australia.

C Corresponding author. Email: mibel.aguilar@monash.edu

Australian Journal of Chemistry 73(4) 366-376 https://doi.org/10.1071/CH19594
Submitted: 17 November 2019  Accepted: 24 January 2020   Published: 2 March 2020

Abstract

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.


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