Inhibition of Bace1 of Alzheimer's Disease by Peptidomimetic Ligands: Computational and Chemical Biology Approach
Posted: 7 Feb 2020
Date Written: February 29, 2020
Abstract
Dementia is a clinical syndrome (a group of co-occurring signs and symptoms) that involves the progressive deterioration of intellectual function. Various cognitive abilities can be impaired with dementia, including memory, reasoning, attention, decision making, visuospatial function and orientation. Alzheimer’s Disease (AD) age-related dementia. Which is caused by Beta site Amyloid precursor protein Cleaving Enzyme 1 (BACE1), It is also called as β-secretase, Asp2 and Memapsin 2 which cleaves a type-I membrane-bound protein called Amyloid precursor protein (APP). The cleavage of APP by BACE1 produces Aβ42 or Aβ40 peptide fragments. The accumulation of Aβ peptides forms Exo cellular plaques called senile plaques and Neurofibrillary tangles in the brain and causes neuronal cell death which leads to dementia and ultimately death. In non-Amyloid pathway APP cleaved by two proteases α-secretes followed by the γ-secretase and produces sAPPβ which is a soluble form of APP. In Amyloid pathway APP is cleaved by α-secretase followed by β-secretase.
Except few, all the enzymatic reactions are stereospecific in nature and they only recognize and cleave the peptide bonds formed by naturally occurring coded amino acids that are L-amino acids. They do not recognize the peptide bonds formed by unnatural amino acids for enzymatic cleavage. APP has many variants such as Wild type, Swedish mutant and so on. It was proved that the Swedish mutant of APP has more affinity towards the BACE1. So we have done modification in the APPsw peptide substrate by changing the chirality of the cleft residues. We have performed the Molecular docking and molecular dynamics simulation of APPsw peptide substrates with BACE1. We synthesized the fluorophore tagged peptide ligands for BACE1 by Solid-phase peptide synthesis employing Fmoc chemistry. The peptide ligands were characterized using RP-HPLC, ESI-MS, FT-IR, CD and fluorescence spectroscopy. We evaluated the inhibitory activity of those peptide ligands against BACE1 using in vitro FRET assay. Our results suggest that the potential development of BACE1 inhibitors containing D-amino acids might lead to progress in making a safe drug for AD.
Keywords: Alzheimer's Disease, BACE1, APP, Peptidomimetic
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