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 in-silico studies to predict the bonding orientation with BACE1. Next, 5 peptides (12, 20, 21, 51, and 52) 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 HNMR spectroscopy. According to their In-vitro BACE1 inhibitory study, peptides 21 having high Vander Waal forces showed significant BACE1 inhibition with IC50 = 4.64 ± 0.1μM). Moreover, the kinetic study revealed that peptide 21 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 in-vivo mice model.