Abstract
Main neuropathological hallmarks of Alzheimers disease (AD) and other neurodegenerative disorders are the deposition of neurofibrillary tangles consisting of abnormally phosphorylated protein tau and of senile plaques largely containing insoluble ß-amyloid peptides (Aß), containing up to 43 amino acid residues derived from the ß-amyloid precursor protein. Such Aß-sheets become visible by using suitable histochemical methods. Molecular simulation showed that the central, α-helical, lipophilic, antigenic folding domain of the Aßpeptide loop is a promising molecular target of ß-sheet breakers that thus prevent the polymerization of Aß into aggregates. It seems that di- and tetramers of Aß-peptides have a ß-barrel- like structure. In the present review, an optimized neural network analysis was applied to recognize possible structureactivity relationships of peptidomimetic ß-sheet breakers. The anti-aggregatory potency of ß-sheet breakers largely depends upon their total, electrostatic, and hydration energy as derived from their geometry-optimized conformations using the hybrid Gasteiger-molecular mechanics approach. Moreover, we also summarize peptide misfolding in several disorders with distinct clinical symptoms, including prion diseases and a broad variety of systemic amyloidoses, as the common pathogenic step driving these disorders. In particular, conversion of nontoxic α-helix / random-coils to ß-sheet conformation was recognized as being critical in producing highly pathogenic peptide assemblies. Whereas conventional pharmacotherapy of AD is mainly focused on restoring cholinergic activity and diminishing inflammatory responses as a consequence of amyloid accumulation, we here survey potential approaches aimed at preventing or reserving the transition of neurotoxic peptide species from α- helical / random coil to ß-sheet conformation and thus abrogating their effects in a broad variety of disorders.
Keywords: Pathological Peptide, Alzheimers Disease, Gasteiger-molecular
Current Medicinal Chemistry
Title: Pathological Peptide Folding in Alzheimers Disease and Other Conformational Disorders
Volume: 9 Issue: 19
Author(s): Peter P. Mager, Botond Penke, Regina Walter, Tibor Harkany and Wolfgang Hartig
Affiliation:
Keywords: Pathological Peptide, Alzheimers Disease, Gasteiger-molecular
Abstract: Main neuropathological hallmarks of Alzheimers disease (AD) and other neurodegenerative disorders are the deposition of neurofibrillary tangles consisting of abnormally phosphorylated protein tau and of senile plaques largely containing insoluble ß-amyloid peptides (Aß), containing up to 43 amino acid residues derived from the ß-amyloid precursor protein. Such Aß-sheets become visible by using suitable histochemical methods. Molecular simulation showed that the central, α-helical, lipophilic, antigenic folding domain of the Aßpeptide loop is a promising molecular target of ß-sheet breakers that thus prevent the polymerization of Aß into aggregates. It seems that di- and tetramers of Aß-peptides have a ß-barrel- like structure. In the present review, an optimized neural network analysis was applied to recognize possible structureactivity relationships of peptidomimetic ß-sheet breakers. The anti-aggregatory potency of ß-sheet breakers largely depends upon their total, electrostatic, and hydration energy as derived from their geometry-optimized conformations using the hybrid Gasteiger-molecular mechanics approach. Moreover, we also summarize peptide misfolding in several disorders with distinct clinical symptoms, including prion diseases and a broad variety of systemic amyloidoses, as the common pathogenic step driving these disorders. In particular, conversion of nontoxic α-helix / random-coils to ß-sheet conformation was recognized as being critical in producing highly pathogenic peptide assemblies. Whereas conventional pharmacotherapy of AD is mainly focused on restoring cholinergic activity and diminishing inflammatory responses as a consequence of amyloid accumulation, we here survey potential approaches aimed at preventing or reserving the transition of neurotoxic peptide species from α- helical / random coil to ß-sheet conformation and thus abrogating their effects in a broad variety of disorders.
Export Options
About this article
Cite this article as:
Mager P. Peter, Penke Botond, Walter Regina, Harkany Tibor and Hartig Wolfgang, Pathological Peptide Folding in Alzheimers Disease and Other Conformational Disorders, Current Medicinal Chemistry 2002; 9 (19) . https://dx.doi.org/10.2174/0929867023369169
DOI https://dx.doi.org/10.2174/0929867023369169 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread 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
-
Organophosphate Induced Delayed Polyneuropathy
Medicinal Chemistry Reviews - Online (Discontinued) Cross Talk between the Cardiovascular and Nervous Systems:Neurotrophic Effects of Vascular Endothelial Growth Factor (VEGF) and Angiogenic Effects of Nerve Growth Factor (NGF)-Implications in Drug Development
Current Pharmaceutical Design Possible Neuroprotective Strategies in ALS
Current Neuropharmacology Effect of Antioxidants on Heavy Metals Induced Conformational Alteration of Cytochrome C and Myoglobin
Protein & Peptide Letters The Molecular Basis of Conantokin Antagonism of NMDA Receptor Function
Current Drug Targets Possibilities of Two-Dimensional Gel Electrophoresis in the Understanding of Human Disease
Current Proteomics An Update on GABA Analogs for CNS Drug Discovery
Recent Patents on CNS Drug Discovery (Discontinued) Antioxidants as a Preventive Treatment for Epileptic Process: A Review of the Current Status
Current Neuropharmacology A Key Role for Connexin Hemichannels in Spreading Ischemic Brain Injury
Current Drug Targets Association of Apolipoprotein E (ApoE) Polymorphism with Alzheimer's Disease in Chinese Population
Current Alzheimer Research Structures Behind the Amyloid Aggregation of α-Synuclein: An NMR based Approach
Current Protein & Peptide Science Systematic Evaluation of Drug-Loaded Hydrogels for Application in Osteosarcoma Treatment
Current Pharmaceutical Biotechnology The Role of local Insulin-like Growth Factor-1 Isoforms in the Pathophysiology of Skeletal Muscle
Current Genomics The Function of the Selective Inhibitors of Cycloxygenase 2
Mini-Reviews in Medicinal Chemistry Blood-based Amyloid and Tau Biomarker Tests For Alzheimer’s Disease
Neuroscience and Biomedical Engineering (Discontinued) APP Transgenic Mouse Models and their Use in Drug Discovery to Evaluate Amyloid-β Lowering Therapeutics
CNS & Neurological Disorders - Drug Targets Therapeutic Management of COVID-19 Patients: Clinical Manifestation and Limitations
Current Pharmaceutical Design Autophagy in the Central Nervous System: Implications for Neurodegenerative Disorders
CNS & Neurological Disorders - Drug Targets Patent Selections
Recent Patents on CNS Drug Discovery (Discontinued) Proteasome Inhibitors Therapeutic Strategies for Cancer
Recent Patents on Anti-Cancer Drug Discovery