Abstract
Since the discovery of phenothiazines as tau protein aggregation inhibitors, many additional small molecule inhibitors of diverse chemotype have been discovered and characterized in biological model systems. Although direct inhibition of tau aggregation has shown promise as a potential treatment strategy for depressing neurofibrillary lesion formation in Alzheimer’s disease, the mechanism of action of these compounds has been unclear. However, recent studies have found that tau aggregation antagonists exert their effects through both covalent and non-covalent means, and have identified associated potency and selectivity driving features. Here we review small-molecule tau aggregation inhibitors with a focus on compound structure and inhibitory mechanism. The elucidation of inhibitory mechanism has implications for maximizing on-target efficacy while minimizing off-target side effects.
Keywords: Alzheimer’s disease, aggregation, neurofibrillary tangle, paired helical filaments, tau.
Current Alzheimer Research
Title:Structure and Mechanism of Action of Tau Aggregation Inhibitors
Volume: 11 Issue: 10
Author(s): Katryna Cisek, Grace L. Cooper, Carol J. Huseby and Jeff Kuret
Affiliation:
Keywords: Alzheimer’s disease, aggregation, neurofibrillary tangle, paired helical filaments, tau.
Abstract: Since the discovery of phenothiazines as tau protein aggregation inhibitors, many additional small molecule inhibitors of diverse chemotype have been discovered and characterized in biological model systems. Although direct inhibition of tau aggregation has shown promise as a potential treatment strategy for depressing neurofibrillary lesion formation in Alzheimer’s disease, the mechanism of action of these compounds has been unclear. However, recent studies have found that tau aggregation antagonists exert their effects through both covalent and non-covalent means, and have identified associated potency and selectivity driving features. Here we review small-molecule tau aggregation inhibitors with a focus on compound structure and inhibitory mechanism. The elucidation of inhibitory mechanism has implications for maximizing on-target efficacy while minimizing off-target side effects.
Export Options
About this article
Cite this article as:
Cisek Katryna, Cooper L. Grace, Huseby J. Carol and Kuret Jeff, Structure and Mechanism of Action of Tau Aggregation Inhibitors, Current Alzheimer Research 2014; 11 (10) . https://dx.doi.org/10.2174/1567205011666141107150331
DOI https://dx.doi.org/10.2174/1567205011666141107150331 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...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
-
Ceramide: Therapeutic Potential in Combination Therapy for Cancer Treatment
Current Drug Metabolism Encountering and Advancing Through Antiangiogenesis Therapy for Gliomas
Current Pharmaceutical Design Targeted Drug Delivery System for Platinum-based Anticancer Drugs
Mini-Reviews in Medicinal Chemistry Potential Role of Acrolein in Neurodegeneration and in Alzheimers Disease
Current Molecular Pharmacology Strategies to Convert PACAP from a Hypophysiotropic Neurohormone Into a Neuroprotective Drug
Current Pharmaceutical Design Adrenergic Drugs Blockers or Enhancers for Cognitive Decline ? What to Choose for Alzheimer’s Disease Patients?
CNS & Neurological Disorders - Drug Targets Discovering Natural Product Modulators to Overcome Multidrug Resistance in Cancer Chemotherapy
Current Pharmaceutical Biotechnology Mutations of Chromatin Structure Regulating Genes in Human Malignancies
Current Protein & Peptide Science PiWi RNA in Neurodevelopment and Neurodegenerative Disorders
Current Molecular Pharmacology Alzheimer’s Disease and Environmental Exposure to Lead: The Epidemiologic Evidence and Potential Role of Epigenetics
Current Alzheimer Research HIV-1 Tat-Mediated Calcium Dysregulation and Neuronal Dysfunction in Vulnerable Brain Regions
Current Drug Targets Development of ATP13A2-deficient In vitro Model for PARK9 Parkinson’s Disease
Current Signal Transduction Therapy Anaplastic Lymphoma Kinase as a Therapeutic Target in Anaplastic Large Cell Lymphoma, Non-Small Cell Lung Cancer and Neuroblastoma
Anti-Cancer Agents in Medicinal Chemistry Colloidal Supramolecular Aggregates for Therapeutic Application in Neuromedicine
Current Medicinal Chemistry Mitochondrial Dysfunctions in Bipolar Disorder: Effect of the Disease and Pharmacotherapy
CNS & Neurological Disorders - Drug Targets The Proline-Rich Domain and the Microtubule Binding Domain of Protein Tau Acting as RNA Binding Domains
Protein & Peptide Letters Diagnostics, Prognostic and Therapeutic Exploitation of Telomeres and Telomerase in Leukemias
Current Pharmaceutical Biotechnology The Ubiquitin Proteasome System as a Potential Target for the Treatment of Neurodegenerative Diseases
Current Pharmaceutical Design Combretastatin A-4 Analogs as Anticancer Agents
Mini-Reviews in Medicinal Chemistry Targeting SKCa Channels in Cancer: Potential New Therapeutic Approaches
Current Medicinal Chemistry