Abstract
γ-secretase is a membrane-embedded aspartyl protease carrying out cleavage of more than 100 single transmembrane-spanning proteins, including APP, Notch, N-cadherin, etc. Its subunit, presenilin (PS) is the catalytic component, of which mutations are a major cause of early onset familial Alzheimer disease (FAD). These mutations lead to an increase in the production of the highly amyloidogenic Aβ42 isoform. Drugs aimed at γ-secretase are now considered to be promising therapeutic targets for AD. γ-secretase inhibitors (GSIs) were first introduced into clinical trials due to their efficacy in lowering Aβ production, but later were found to cause severe adverse events due to their blockage of the Notch signaling process. γ-secretase modulators (GSMs) were developed to modulate γ-secretase activity by selectively targeting Aβ42 reduction over the Notch pathway, which have been shown to have less side effects. Although clinical studies show that none of the GSIs or GSMs have been proven to be fully effective, they shed light on the physiological role of γ-secretase and PS in AD development. At the same time, natural products, due to their structural diversity and pleiotropic profile, can modulate γ-secretase activity in a dose-dependent manner, broadening our vision of drug development. With the structural information of γ-secretase released recently, we speculate there will be an explosion of γ-secretase modulators targeting not only the proteolysic center but also the interaction of its different components.
Keywords: Alzheimer disease, γ-secretase inhibitors, γ-secretase modulators, Natural products, Presenilin.
Current Topics in Medicinal Chemistry
Title:Anti-Alzheimer Therapeutic Drugs Targeting γ-Secretase
Volume: 16 Issue: 5
Author(s): Yan Tan, Qi Zhang, Steven G. Wong and Qian Hua
Affiliation:
Keywords: Alzheimer disease, γ-secretase inhibitors, γ-secretase modulators, Natural products, Presenilin.
Abstract: γ-secretase is a membrane-embedded aspartyl protease carrying out cleavage of more than 100 single transmembrane-spanning proteins, including APP, Notch, N-cadherin, etc. Its subunit, presenilin (PS) is the catalytic component, of which mutations are a major cause of early onset familial Alzheimer disease (FAD). These mutations lead to an increase in the production of the highly amyloidogenic Aβ42 isoform. Drugs aimed at γ-secretase are now considered to be promising therapeutic targets for AD. γ-secretase inhibitors (GSIs) were first introduced into clinical trials due to their efficacy in lowering Aβ production, but later were found to cause severe adverse events due to their blockage of the Notch signaling process. γ-secretase modulators (GSMs) were developed to modulate γ-secretase activity by selectively targeting Aβ42 reduction over the Notch pathway, which have been shown to have less side effects. Although clinical studies show that none of the GSIs or GSMs have been proven to be fully effective, they shed light on the physiological role of γ-secretase and PS in AD development. At the same time, natural products, due to their structural diversity and pleiotropic profile, can modulate γ-secretase activity in a dose-dependent manner, broadening our vision of drug development. With the structural information of γ-secretase released recently, we speculate there will be an explosion of γ-secretase modulators targeting not only the proteolysic center but also the interaction of its different components.
Export Options
About this article
Cite this article as:
Tan Yan, Zhang Qi, Wong G. Steven and Hua Qian, Anti-Alzheimer Therapeutic Drugs Targeting γ-Secretase, Current Topics in Medicinal Chemistry 2016; 16 (5) . https://dx.doi.org/10.2174/1568026615666150813144151
DOI https://dx.doi.org/10.2174/1568026615666150813144151 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
AlphaFold in Medicinal Chemistry: Opportunities and Challenges
AlphaFold, a groundbreaking AI tool for protein structure prediction, is revolutionizing drug discovery. Its near-atomic accuracy unlocks new avenues for designing targeted drugs and performing efficient virtual screening. However, AlphaFold's static predictions lack the dynamic nature of proteins, crucial for understanding drug action. This is especially true for multi-domain proteins, ...read more
Artificial intelligence for Natural Products Discovery and Development
Our approach involves using computational methods to predict the potential therapeutic benefits of natural products by considering factors such as drug structure, targets, and interactions. We also employ multitarget analysis to understand the role of drug targets in disease pathways. We advocate for the use of artificial intelligence in predicting ...read more
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Chronic Kidney Disease
The scope of the special thematic issue includes but not limited to the mechanism of chronic kidney disease (CKD), the treatment of renal fibrosis and early diagnosis of CKD and so on. We also welcome manuscripts from other scientific research area with respect to internal medicine. Cell death has been ...read more
![](/images/wayfinder.jpg)
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Current Experimental Therapy for Alzheimers Disease
Current Neuropharmacology Clearance of Amyloid-β Peptide Across the Blood-Brain Barrier: Implication for Therapies in Alzheimers Disease
CNS & Neurological Disorders - Drug Targets Recent Approaches Targeting Beta-Amyloid for Therapeutic Intervention of Alzheimer's disease
Recent Patents on CNS Drug Discovery (Discontinued) Antifungal Activity of Plant Secondary Metabolites on <i>Candida albicans</i>: An Updated Review
Current Molecular Pharmacology Virus-Associated Vasculitides: An Update
Current Immunology Reviews (Discontinued) Anti-Viral Agents in Neurodegenerative Disorders: New Paradigm for Targeting Alzheimer’s Disease
Recent Patents on Anti-Infective Drug Discovery Efficacy and Toxicity of Clioquinol Treatment and A-beta42 Inoculation in the APP/PSI Mouse Model of Alzheimer's Disease
Current Alzheimer Research Herpetic (Non-Cytomegalovirus) Retinal Infections in Patients with the Acquired Immunodeficiency Syndrome
Current HIV Research Pyroglutamate-Modified Amyloid Beta Peptides: Emerging Targets for Alzheimer´s Disease Immunotherapy
Current Neuropharmacology An Update on Autoinflammatory Diseases
Current Medicinal Chemistry Rationale for Peptide and DNA Based Epitope Vaccines for Alzheimers Disease Immunotherapy
CNS & Neurological Disorders - Drug Targets Alternative Aβ Immunotherapy Approaches for Alzheimers Disease
CNS & Neurological Disorders - Drug Targets Clear Shot at Primary Aim: Susceptibility of Trypanosoma cruzi Organelles, Structures and Molecular Targets to Drug Treatment
Current Topics in Medicinal Chemistry Global Warming Favors Pathogenicity of the Brain-Eating Amoebae
Anti-Infective Agents Therapeutic Modulation of Cytokines in Chronic Infectious Diseases
Current Pharmaceutical Design Pneumonia in Lung Transplant Recipients
Current Respiratory Medicine Reviews Antiproliferative and Antifungal Activities of 1,3-diarylpropane-1,3-diones Commonly used as Sunscreen Agents
Letters in Drug Design & Discovery Alzheimers Disease and Immunotherapy
Current Alzheimer Research Critical Issues for Successful Immunotherapy in Alzheimers Disease: Development of Biomarkers and Methods for Early Detection and Intervention
CNS & Neurological Disorders - Drug Targets Borna Disease Virus (BDV): Neuropharmacological Effects of a CNS Viral Infection
Current Neuropharmacology