Title:Role of γ-Secretase Inhibitors for the Treatment of Diverse Disease Conditions through Inhibition of Notch Signaling Pathway
Volume: 22
Issue: 15
关键词:
β-淀粉样蛋白前体、γ-分泌酶抑制剂、缺口信号、缺口配体、自身免疫性淋巴组织增生综合征 (ALPS)、血管生成。
摘要: γ-secretase is an intramembrane protease sub-assembly that sunders transmembrane proteins.
It is involved in intramembrane proteolysis and also contributes to the regeneration of transmembrane
protein. The amyloid precursor proteins (APPs) are typical γ-secretase substrates. These
proteins are cleaved to produce 36-43 amyloid-beta (Aβ) amino acid peptides. Abnormal folding of
these proteins fragments leads to amyloid plaques, which are frequently encountered in
Alzheimer’s disease. Some Type I class of integral membrane proteins is processed under the influence
of γ-secretase, such as receptor tyrosine-protein kinase erbB4 and CD44 glycoprotein. γ-Secretase
is being explored in several 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 lack sufficient potency,
exhibit low penetration in the brain, and manifest low selectiveness. γ-secretase inhibitors are
obliquely a regulator of a γ-secretase substrate Notch, and valuable in the development of β-amyloid
peptide (Aβ). These γ-secretase inhibitors block the Notch signaling pathway in autoimmune
and lymphoproliferative disorders, like autoimmune lymphoproliferative syndrome (ALPS) and
systemic lupus erythematosus (SLE), and perhaps even in cancerous cell proliferation, angiogenesis,
and cellular differentiation of human-induced pluripotent stem cells (hiPSC). The current review
portrays the mechanism, regulation, and inhibition of γ-secretase in the management of a
wide assortment of diseases.
