Abstract
Despite decades of research, therapy for diseases caused by abnormal protein folding and aggregation (amyloidoses) is limited to treatment of symptoms and provides only temporary and moderate relief to sufferers. The failure in developing successful diseasemodifying drugs for amyloidoses stems from the nature of the targets for such drugs – primarily oligomers of amyloidogenic proteins, which are distinct from traditional targets, such as enzymes or receptors. The oligomers are metastable, do not have well-defined structures, and exist in dynamically changing mixtures. Therefore, inhibiting the formation and toxicity of these oligomers likely will require out-of-the-box thinking and novel strategies. We review here the development of a strategy based on targeting the combination of hydrophobic and electrostatic interactions that are key to the assembly and toxicity of amyloidogenic proteins using lysine (K)-specific “molecular tweezers” (MTs). Our discussion includes a survey of the literature demonstrating the important role of K residues in the assembly and toxicity of amyloidogenic proteins and the development of a lead MT derivative called CLR01, from an inhibitor of protein aggregation in vitro to a drug candidate showing effective amelioration of disease symptoms in animal models of Alzheimer's and Parkinson's diseases.
Keywords: Amyloid, Alzheimer's disease, Parkinson's disease, inhibitor, oligomer, lysine, molecular tweezers.
Current Pharmaceutical Design
Title:Disrupting Self-Assembly and Toxicity of Amyloidogenic Protein Oligomers by “ Molecular Tweezers” - from the Test Tube to Animal Models
Volume: 20 Issue: 15
Author(s): Aida Attar and Gal Bitan
Affiliation:
Keywords: Amyloid, Alzheimer's disease, Parkinson's disease, inhibitor, oligomer, lysine, molecular tweezers.
Abstract: Despite decades of research, therapy for diseases caused by abnormal protein folding and aggregation (amyloidoses) is limited to treatment of symptoms and provides only temporary and moderate relief to sufferers. The failure in developing successful diseasemodifying drugs for amyloidoses stems from the nature of the targets for such drugs – primarily oligomers of amyloidogenic proteins, which are distinct from traditional targets, such as enzymes or receptors. The oligomers are metastable, do not have well-defined structures, and exist in dynamically changing mixtures. Therefore, inhibiting the formation and toxicity of these oligomers likely will require out-of-the-box thinking and novel strategies. We review here the development of a strategy based on targeting the combination of hydrophobic and electrostatic interactions that are key to the assembly and toxicity of amyloidogenic proteins using lysine (K)-specific “molecular tweezers” (MTs). Our discussion includes a survey of the literature demonstrating the important role of K residues in the assembly and toxicity of amyloidogenic proteins and the development of a lead MT derivative called CLR01, from an inhibitor of protein aggregation in vitro to a drug candidate showing effective amelioration of disease symptoms in animal models of Alzheimer's and Parkinson's diseases.
Export Options
About this article
Cite this article as:
Attar Aida and Bitan Gal, Disrupting Self-Assembly and Toxicity of Amyloidogenic Protein Oligomers by “ Molecular Tweezers” - from the Test Tube to Animal Models, Current Pharmaceutical Design 2014; 20 (15) . https://dx.doi.org/10.2174/13816128113199990496
DOI https://dx.doi.org/10.2174/13816128113199990496 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...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
-
Glycosaminoglycans, Protein Aggregation and Neurodegeneration
Current Protein & Peptide Science Bilateral Interrelationship of Diabetes and Periodontium
Current Diabetes Reviews Dasatinib: An Anti-Tumour Agent via Src Inhibition
Current Drug Targets Conformations and Biological Activities of Amyloid Beta Peptide 25-35
Current Protein & Peptide Science Screening of Early and Late Onset Alzheimer’s Disease Genetic Risk Factors in a Cohort of Dementia Patients from Liguria, Italy
Current Alzheimer Research Liver X Receptor-Mediated Gene Regulation and Cholesterol Homeostasis in Brain: Relevance to Alzheimers Disease Therapeutics
Current Alzheimer Research The Ultra High Risk Approach to Define Psychosis Risk
Current Pharmaceutical Design Autonomic Sudomotor Dysfunction in Alzheimers Disease
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents Peptides and their Metal Complexes in Neurodegenerative Diseases: from Structural Studies to Nanomedicine Prospects
Current Medicinal Chemistry Glycaemic Control: A Balancing Act or A Different Approach?
Current Diabetes Reviews An Appraisal of Current Pharmacological Perspectives of Sesamol: A Review
Mini-Reviews in Medicinal Chemistry Recent Advances in Progressive Supranuclear Palsy: A Review
Current Alzheimer Research Alzheimer’s Disease – Future Therapy Based on Dendrimers
Current Neuropharmacology Chemistry and Biology of Thyrotropin-Releasing Hormone (TRH) and its Analogs
Current Medicinal Chemistry Blockade of Renin Angiotensin System in Heart Failure Post-Myocardial Infarction: What is the Best Therapy?
Recent Patents on Cardiovascular Drug Discovery End-Stage Dementia Spark of Life: Reliability and Validity of the “GATOS” Questionnaire
Current Alzheimer Research Microalbuminuria: A Neglected Cardiovascular Risk Factor in Non-diabetic Individuals?
Current Pharmaceutical Design Default Mode Network Connectivity and Related White Matter Disruption in Type 2 Diabetes Mellitus Patients Concurrent with Amnestic Mild Cognitive Impairment
Current Alzheimer Research Amphetamine Use in the Elderly: A Systematic Review of the Literature
Current Neuropharmacology Consensus Guideline Based Therapeutic Drug Monitoring (TDM) in Psychiatry and Neurology
Current Drug Delivery