Abstract
γ-secretase is an aspartyl protease that cleaves a large number of substrates within the membrane environment. This multiprotein complex is responsible for the last cleavage step of the β-amyloid precursor protein (APP) that generates the amyloid-β peptide (Aβ), one of the primary components of amyloid plaques in Alzheimer's disease (AD). Over the last years, more than 90 type-I membrane proteins have been shown to be cleaved by γ-secretase. The mechanism and function of this cleavage event is not yet well understood. The -secretase cleavage of some substrates releases intracellular domains with critical signaling properties. In contrast, the cleavage of other substrates seems to have a mere degradative function. Knowledge about γ-secretase substrates and their function has clear implications for the development of new therapies for AD. Most γ-secretase inhibitors interfere with the cleavage of the Notch receptor, which is known to lead to adverse effects in animal models and in humans. Paradoxically, due to this effect, γ-secretase inhibitors are actively being investigated in cancer. An alternative approach is modulation of γ-secretase, in which small molecules allosterically attenuate the activity to reduce Aβ42, the most fibrillogenic species. Although tolerance and efficacy of some γ-secretase inhibitors in AD have shown to be poor in clinical trials, more selective compounds are on the road. As these compounds advance to clinical trials it is critical to understand the mechanism by which γ-secretase recognizes and cleaves this diverse set of substrates to predict possible adverse effects in humans. This knowledge will help to guide drug development in AD and cancer.
Keywords: Alzheimer's, amyloid-β, memory, notch receptor, presenilin, γ-secretase substrates, secretase substrates, multiprotein complex, cancer, fibrillogenic species, tolerance and efficacy of some -secretase, adverse effects
Current Topics in Medicinal Chemistry
Title: γ-Secretase Substrates and their Implications for Drug Development in Alzheimer's Disease
Volume: 11 Issue: 12
Author(s): Alberto Lleo and Carlos A. Saura
Affiliation:
Keywords: Alzheimer's, amyloid-β, memory, notch receptor, presenilin, γ-secretase substrates, secretase substrates, multiprotein complex, cancer, fibrillogenic species, tolerance and efficacy of some -secretase, adverse effects
Abstract: γ-secretase is an aspartyl protease that cleaves a large number of substrates within the membrane environment. This multiprotein complex is responsible for the last cleavage step of the β-amyloid precursor protein (APP) that generates the amyloid-β peptide (Aβ), one of the primary components of amyloid plaques in Alzheimer's disease (AD). Over the last years, more than 90 type-I membrane proteins have been shown to be cleaved by γ-secretase. The mechanism and function of this cleavage event is not yet well understood. The -secretase cleavage of some substrates releases intracellular domains with critical signaling properties. In contrast, the cleavage of other substrates seems to have a mere degradative function. Knowledge about γ-secretase substrates and their function has clear implications for the development of new therapies for AD. Most γ-secretase inhibitors interfere with the cleavage of the Notch receptor, which is known to lead to adverse effects in animal models and in humans. Paradoxically, due to this effect, γ-secretase inhibitors are actively being investigated in cancer. An alternative approach is modulation of γ-secretase, in which small molecules allosterically attenuate the activity to reduce Aβ42, the most fibrillogenic species. Although tolerance and efficacy of some γ-secretase inhibitors in AD have shown to be poor in clinical trials, more selective compounds are on the road. As these compounds advance to clinical trials it is critical to understand the mechanism by which γ-secretase recognizes and cleaves this diverse set of substrates to predict possible adverse effects in humans. This knowledge will help to guide drug development in AD and cancer.
Export Options
About this article
Cite this article as:
Lleo Alberto and A. Saura Carlos, γ-Secretase Substrates and their Implications for Drug Development in Alzheimer's Disease, Current Topics in Medicinal Chemistry 2011; 11 (12) . https://dx.doi.org/10.2174/156802611795861004
DOI https://dx.doi.org/10.2174/156802611795861004 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
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
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- 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
-
The Enzymology of Cytosolic Pyrimidine 5’-Nucleotidases: Functional Analysis and Physiopathological Implications.
Current Medicinal Chemistry Phenothiazines and Related Drugs as Multi Drug Resistance Reversal Agents in Cancer Chemotherapy Mediated by p-glycoprotein
Current Cancer Therapy Reviews A New Era of Pulmonary Delivery of Nano-antimicrobial Therapeutics to Treat Chronic Pulmonary Infections
Current Pharmaceutical Design Targeting of Adhesion Molecules as a Therapeutic Strategy in Multiple Myeloma
Current Cancer Drug Targets Insights into a Critical Role of the FOXO3a-FOXM1 Axis in DNA Damage Response and Genotoxic Drug Resistance
Current Drug Targets ATP Site-Directed Inhibitors of Protein Kinase CK2: An Update
Current Topics in Medicinal Chemistry Recent Advances in Epitope Design for Immunotherapy of Cancer
Recent Patents on Anti-Cancer Drug Discovery Anticancer Drugs Discovery and Development from Marine Organisms
Current Topics in Medicinal Chemistry miRNAs Highlights in Stem and Cancer Cells
Mini-Reviews in Medicinal Chemistry Quercetin Promotes Cell Cycle Arrest and Apoptosis and Attenuates the Proliferation of Human Chronic Myeloid Leukemia Cell Line-K562 Through Interaction with HSPs (70 and 90), MAT2A and FOXM1
Anti-Cancer Agents in Medicinal Chemistry The Role of DNA Repair Pathways in AML Chemosensitivity
Current Drug Targets α-Halogenoacrylic Derivatives of Antitumor Agents
Mini-Reviews in Medicinal Chemistry Microarrays as a Tool for Gene Expression Profiling: Application in Ocular and Craniofacial Research
Current Pharmaceutical Analysis Azathioprine in Multiple Sclerosis
Mini-Reviews in Medicinal Chemistry Epigenetics and Adult Acute Myeloid Leukemia
Current Pharmacogenomics and Personalized Medicine Intracellular Restriction Factors In Mammalian Cells - An Ancient Defense System Finds A Modern Foe
Current HIV Research Isoindole Derivatives: Propitious Anticancer Structural Motifs
Current Topics in Medicinal Chemistry Signal Transduction Pathways and Transcriptional Mechanisms as Targets for Prevention of Emergence of Multidrug Resistance in Human Cancer Cells
Current Drug Targets T Cell Tuning for Tumour Therapy: Enhancing Effector Function and Memory Potential of Therapeutic T cells
Current Gene Therapy Clinical Applications and Biosafety of Human Adult Mesenchymal Stem Cells
Current Pharmaceutical Design