Role of γ-Secretase Inhibitors for the Treatment of Diverse Disease Conditions through Inhibition of Notch Signaling Pathway

Curr Drug Targets. 2021 May 15. doi: 10.2174/1389450122666210515161312. Online ahead of print.ABSTRACTγ-Secretase is an intramembrane protease sub-assembly which that sunders transmembrane proteins. They are involved in intramembrane proteolysis and also contribute to the regeneration of transmembrane protein. The amyloid precursor protein (APP) is a typical γ-secretase substrate. These proteins are cleaved to produce 36-43 amyloid-beta (Aβ) amino acid peptides. Abnormal folding of these protein fragments leads to amyloid plaques; , frequently encountered in Alzheimer's disease. Some Type I class of integral membrane proteins are processed under the influence of γ-secretase, such as receptor tyrosine-protein kinase erbB4 and CD44 glycoprotein. γ-Secretase is being explored in a number of diseases as a clinical goal. Both γ-secretase inhibitors (GSIs) and γ-secretase modulators (GSMs) are being evaluated for this purpose. A large amount of γ-secretase inhibitors (GSIs) from peptide to non-peptide have been disclosed, offering several lead compounds for the design and optimization of γ-secretase targets, but most GSIs lacks sufficient potency, low penetration in the brain, and low selectiveness. γ-Secretase inhibitors are obliquely a regulator of a γ-secretase substrate Notch, and valuable in the understanding of the development of β-amyloid peptide (Aβ). These γ-secretase inhibitors block the Notch signaling pathway in autoimmune and lymphoproliferative disorders...
Source: Current Drug Targets - Category: Drugs & Pharmacology Authors: Source Type: research