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image of Discovery of Selective β-Secretase (BACE-1) Inhibitors by the Solid-Phase Synthesis of Small Molecular-sized Peptides

Abstract

Introduction

Alzheimer's disease (AD) is a progressive neurological disorder for which no effective cure currently exists. Research has identified β-Secretase (BACE1) as a promising therapeutic target for the management of AD. BACE1 is involved in the rate-limiting step and produces toxic amyloid-beta (Aβ) peptides that lead to deposits in the form of amyloid plaques extracellularly, resulting in AD.

Method

In this connection, 60 small peptides were evaluated for their studies to predict the bonding orientation with BACE1. Next, 5 peptides ( and were selected based on high scoring of Vander Waal interactions with the catalytic site of the enzyme.

Results

The identified hit peptides were synthesized using Solid-Phase Peptide Synthesis (SPPS), and Electrospray Ionization Mass Spectrometry (ESI-MS) elucidated their structures and 1 1 H-NMR spectroscopy. According to their BACE1 inhibitory study, peptides having high Vander Waal forces showed significant BACE1 inhibition with IC = 4.64 ± 0.1µM). Moreover, the kinetic study revealed that peptide is a mixed-type inhibitor and can interact at the active site and the allosteric site of BACE1.

Conclusion

According to the cytotoxicity study, peptide 21 was found to be noncytotoxic at 4.64 µM, 10 µM and 20 µM. The forthcoming target of this study is to evaluate further the effect of peptide 21 in an mice model.

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2025-02-10
2025-03-27

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/content/journals/car/10.2174/0115672050336253241227102506
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Discovery of Selective β-Secretase (BACE-1) Inhibitors by the Solid-Phase Synthesis of Small Molecular-sized Peptides
Bentham Science Publishers ; https://doi.org/10.2174/0115672050336253241227102506
/content/journals/car/10.2174/0115672050336253241227102506
/content/journals/car/10.2174/0115672050336253241227102506
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  • Article Type:     Research Article
Keywords: Alzheimer's disease ; β-secretase (BACE1) ; ESI-MS ; peptides synthesis ; in-vitro ; in silico ; 1H-NMR

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