Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Abstract

The continual increase of the aging population worldwide renders Alzheimer's disease (AD) a global prime concern. Several attempts have been focused on understanding the intricate complexity of the disease's development along with the on‐ andgoing search for novel therapeutic strategies. Incapability of existing AD drugs to effectively modulate the pathogenesis or to delay the progression of the disease leads to a shift in the paradigm of AD drug discovery. Efforts aimed at identifying AD drugs have mostly focused on the development of disease‐modifying agents in which effects are believed to be long lasting. Of particular note, the secretase enzymes, a group of proteases responsible for the metabolism of the β‐amyloid precursor protein (βAPP) and β‐amyloid (Aβ) peptides production, have been underlined for their promising therapeutic potential. This review article attempts to comprehensively cover aspects related to the identification and use of drugs targeting the secretase enzymes. Particularly, the roles of secretases in the pathogenesis of AD and their therapeutic modulation are provided herein. Moreover, an overview of the drug development process and the contribution of computational (in silico) approaches for facilitating successful drug discovery are also highlighted along with examples of relevant computational works. Promising chemical scaffolds, inhibitors, and modulators against each class of secretases are also summarized herein. Additionally, multitarget secretase modulators are also taken into consideration in light of the current growing interest in the polypharmacology of complex diseases. Finally, challenging issues and future outlook relevant to the discovery of drugs targeting secretases are also discussed.

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

“…This necessitates the need for the design of diverse molecular libraries with high 3D‐content to crosstalk specifically with the high 3D‐content complementary in BACE1. This conclusion is supported by several examples of successful drug discoveries, which indicated that increasing the SP 3 ‐contents of a ligand to better suit the complementary binding regions of an active site correlates favorably with selectivity and the success rate in clinical trials . Moreover, recent reports illustrated that BACE1 inhibitors caused structural and functional synaptic impairment that accounts for safety concerns .…”

“…This conclusion is supported by several examples of successful drug discoveries, which indicated that increasing the SP 3 -contents of a ligand to better suit the complementary binding regions of an active site correlates favorably with selectivity and the success rate in clinical trials. [195][196][197] Moreover, recent reports illustrated that BACE1 inhibitors caused structural and functional synaptic impairment that accounts for safety concerns. 106 Additionally, emerging evidence is exposing gender as a factor to be considered when designing therapeutic option for AD, 198 which requires further investigations to determine how this element can better shape AD therapy.…”

Rhodiola crenulata protects against Alzheimer's disease in rats: A brain lipidomics study by Fourier‐transform ion cyclotron resonance mass spectrometry coupled with high‐performance reversed‐phase liquid chromatography and hydrophilic interaction liquid chromatography

“…Alzheimer's disease (AD) is a degenerative brain disease that poses an enormous economic and healthcare burden on society 1,2 . AD has been extensively investigated in modern medicine and communities worldwide.…”

“…AD has been extensively investigated in modern medicine and communities worldwide. Currently, several targeted therapeutic strategies, including acetylcholinesterase inhibitors, β‐site amyloid precursor protein cleaving enzyme‐1 inhibitors, and N‐methyl‐D‐aspartate receptor antagonists, have been used clinically to alleviate the symptoms of AD 2–5 . However, there is currently no drug that can reverse the mechanisms underlying AD.…”

DataSheet1.pdf

“…So far, however, compared with placebo in clinical trials, these monotherapies have failed to affect disease progression or symptoms (Dodel et al, 2003;Godyn et al, 2016;Panza et al, 2019). Recently, the scientists believe that combination therapy might be better than monotherapy (Bachurin et al, 2017;Sahoo et al, 2018;Cummings et al, 2019;Schaduangrat et al, 2019). However, the complex pathophysiology of AD makes the design of combination therapy more difficult.…”