Natural Compounds with Anti-BACE1 Activity as Promising Therapeutic Drugs for Treating Alzheimerʼs Disease

Abstract

Alzheimerʼs disease is a neurodegenerative disease that leads to irreversible neuronal damage. Senile plaques, composed of amyloid beta peptide, is the principal abnormal characteristic of the disease. Among the factors involved, the secretase enzymes, namely, α secretase, beta-site amyloid precursor protein-cleaving enzyme, β secretase, and γ secretase, hold consequential importance. Beta-site amyloid precursor protein-cleaving enzyme 1 is considered to be the rate-limiting factor in the production of amyloid beta peptide. Research supporting the concept of inhibition of beta-site amyloid precursor protein-cleaving enzyme activity as one of the effective therapeutic targets in the mitigation of Alzheimerʼs disease is well accepted. The identification of natural compounds, such as β-amyloid precursor protein-selective beta-site amyloid precursor protein-cleaving enzyme inhibitors, and the idea of compartmentalisation of the beta-site amyloid precursor protein-cleaving enzyme 1 action have caused a dire need to closely examine the natural compounds and their effectiveness in the disease mitigation. Many natural compounds have been reported to effectively modulate beta-site amyloid precursor protein-cleaving enzyme 1. At lower doses, compounds like 2,2′,4′-trihydroxychalcone acid, quercetin, and myricetin have been shown to effectively reduce beta-site amyloid precursor protein-cleaving enzyme 1 activity. The currently used five drugs that are marketed and used for the management of Alzheimerʼs disease have an increased risk of toxicity and restricted therapeutic efficiency, hence, the search for new anti-Alzheimerʼs disease drugs is of primary concern. A variety of natural compounds having pure pharmacological moieties showing multitargeting activity and others exhibiting specific beta-site amyloid precursor protein-cleaving enzyme 1 inhibition as discussed below have superior biosafety. Many of these compounds, which are isolated from medicinal herbs and marine flora, have been long used for the treatment of various ailments since ancient times in the Chinese and Ayurvedic medical systems. The aim of this article is to review the available data on the selected natural compounds, giving emphasis to the inhibition of beta-site amyloid precursor protein-cleaving enzyme 1 activity as a mode of Alzheimerʼs disease treatment.

The Effect of Sacred Lotus (Nelumbo nucifera) and Its Mixtures on Phenolic Profiles, Antioxidant Activities, and Inhibitions of the Key Enzymes Relevant to Alzheimer’s Disease

“…Non-peptidic BACE-1 inhibitors were previously reported to be small-sized compounds such as hydroxymethylcarbonyl (HMC) isostere, which is a substrate transition-state mimic in BACE-1 reaction [ 49 ], as well as chemotypes including aminohydantoin, aminooxazolines, and aminothiazolines that were designed based on interactions with the enzyme active site [ 50 ]. Phenolics have also been proven to act as BACE-1 inhibitors [ 51 ]. Naringenin was reported to inhibit BACE-1 activity with the IC 50 value of 30.31 µM [ 43 ], while quercetin, a stronger BACE-1 inhibitor, exhibited the IC 50 value of 5.4 µM [ 52 ].…”

Polyphenols in Alzheimer’s Disease and in the Gut–Brain Axis

“…Polyphenolic compounds are a diverse class of phenolic compounds that include flavanoids, such as epigallocatechin, epigallocatechin gallate, and catechin, and flavonoids, such as quercetin, fisetin, and luteolin, as pharmaceutically important compounds [1][2][3][4]. Quercetin and related flavonoids are β-amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitors [5]. Flavanoids as well as non-steroidal anti-inflammatory agents (NSAIDS) modulate the nuclear factor-kappa β (NF-κB) signaling pathways, and thereby are potential therapeutic targets for neurodegenerative diseases, such as AD and Parkinson's disease (PD) [2].…”

Marine Cyanobacteria: A Source of Lead Compounds and their Clinically-Relevant Molecular Targets

“…Tasiamide B Tasiamide B (41) (Figure 7) is a statine-containing linear depsipeptide shown to inhibit the aspartic protease, BACE1, with an IC 50 of 0.19 µM [105,109]. BACE1, also known as β-secretase 1, is a potential drug target for the treatment of Alzheimer's disease (AD) due to its involvement in the abnormal production of β-amyloid plaques in AD patients [110,111]. The total synthesis of tasiamide B led to a revision in stereochemistry on the structure of the original reported molecule [112].…”