Small Molecular Weight Compounds Antagonistic to Amyloid Peptide&amp;lt;sub&amp;gt;25-35&amp;lt;/sub&amp;gt;

W Robert Williams

doi:10.4236/jbm.2021.91004

Abstract

High levels of the neurotoxic beta-amyloid protein (Aβ) in patients with Alzheimer’s disease present a significant therapeutic target, although the protein is unlikely to be the sole instigator of this condition. Aβ initiates cell receptor and synapse dysfunction, and causes mitochondrial damage within neurons. Neurotransmitters and various small molecular weight compounds ameliorate the effects of Aβ on cell membranes. This study uses a molecular modeling technique to compare the structures of Aβ25-35 and compounds known to antagonize properties of the polypeptide. Compounds provide good fits to the peptide amino acid residues, revealing planarity in their linear structures and fitting points. Compounds and polypeptide share relative molecular similarity, affinity for receptors and apoptosis modulating properties indicative of their potential for competition at neuron membrane sites. The therapeutic targeting of Aβ by small molecular weight compounds may benefit from a multi-drug approach.

Highlights

In past decades, beta-amyloid protein (Aβ) has been a main focus of diagnostic and therapeutic strategies seeking to prevent the histological and neurochemical changes of Alzheimer’s disease (AD) [1]
This study uses a molecular modeling technique to compare the structures of Aβ25-35 and compounds known to antagonize properties of the polypeptide
Several classes of cell receptor are susceptible to desensitization, internalisation or activation by Aβ: adrenergic, NMDA and α7-nicotinic acid (α-7nACh) receptors [5] [6]

Summary

Introduction

Beta-amyloid protein (Aβ) has been a main focus of diagnostic and therapeutic strategies seeking to prevent the histological and neurochemical changes of Alzheimer’s disease (AD) [1]. Picomolar concentrations of oligomeric Aβ modulate pre- and post-synaptic mechanisms, augmenting neurotransmitter release and facilitating early to late long-term potentiation (LTP) transition via α7-nAchR and the NO/cGMP pathway [11]. This more favourable view of Aβ complements the knowledge that platelets are a major source of amyloid precursor protein [12]. Of pertinence to this study are observations that the above small molecular weight compounds modulate cell apoptosis and induce oxidative stress irrespective of the presence of Aβ [33]. Williams membrane receptors and antagonism of neurotoxicity by small molecular weight compounds

Methods

Results

Discussion