Abstract
Nuclear Factor-Kappa B (NF-κB) is a transcription factor whose inappropriate activation may result in the development of a number of diseases including cancer, inflammation, neurodegeneration and AIDS. Recent studies on NF- κB mediated pathologies, made therapeutic interventions leading to its inhibition an emerging theme in pharmaceutical research. NF-κB resides in the cytoplasm and is activated by several time-dependent factors, leading to proteasomedependent degradation of its inhibitory protein (IκB), resulting in free NF-κB (p50 and p65 subunits, involved in disease states), which binds to target DNA sites, further resulting in enhanced transcription of several disease associated proteins. The complex pathway of NF-κB, finally leading to its DNA binding, has attracted several approaches interfering with this pathway. One such approach is that of a direct covalent modification of NF-κB. In this article, we present a critical review of the pharmacological agents that have been studied as inhibitors of NF-κB by covalently modifying redox-regulated cysteine residues in its subunits, ultimately resulting in the inhibition of κB DNA recognition and binding. Beginning with a general overview of NF-κB pathway and several possibilities of chemical interventions, the significance of redoxregulation in NF-κB activation and DNA binding is presented. Further, protein S-thiolation, S-nitrosylation and irreversible covalent modification are described as regular biochemical events in the cell, having provided a guideline for the development of NF-κB inhibitors discussed further. Although just a handful of inhibitors, with most of them being alkylating agents have been studied in the present context, this approach presents potential for the development of a new class of NF-κB-inhibitors.
Keywords: Nuclear Factor-Kappa B, Cysteine, S-thiolation, S-nitrosylation, Covalent Modification, Alkylating Agents
Current Medicinal Chemistry
Title: Direct Covalent Modification as a Strategy to Inhibit Nuclear Factor-Kappa B
Volume: 16 Issue: 32
Author(s): V. Pande, S. F. Sousa and M. J. Ramos
Affiliation:
Keywords: Nuclear Factor-Kappa B, Cysteine, S-thiolation, S-nitrosylation, Covalent Modification, Alkylating Agents
Abstract: Nuclear Factor-Kappa B (NF-κB) is a transcription factor whose inappropriate activation may result in the development of a number of diseases including cancer, inflammation, neurodegeneration and AIDS. Recent studies on NF- κB mediated pathologies, made therapeutic interventions leading to its inhibition an emerging theme in pharmaceutical research. NF-κB resides in the cytoplasm and is activated by several time-dependent factors, leading to proteasomedependent degradation of its inhibitory protein (IκB), resulting in free NF-κB (p50 and p65 subunits, involved in disease states), which binds to target DNA sites, further resulting in enhanced transcription of several disease associated proteins. The complex pathway of NF-κB, finally leading to its DNA binding, has attracted several approaches interfering with this pathway. One such approach is that of a direct covalent modification of NF-κB. In this article, we present a critical review of the pharmacological agents that have been studied as inhibitors of NF-κB by covalently modifying redox-regulated cysteine residues in its subunits, ultimately resulting in the inhibition of κB DNA recognition and binding. Beginning with a general overview of NF-κB pathway and several possibilities of chemical interventions, the significance of redoxregulation in NF-κB activation and DNA binding is presented. Further, protein S-thiolation, S-nitrosylation and irreversible covalent modification are described as regular biochemical events in the cell, having provided a guideline for the development of NF-κB inhibitors discussed further. Although just a handful of inhibitors, with most of them being alkylating agents have been studied in the present context, this approach presents potential for the development of a new class of NF-κB-inhibitors.
Export Options
About this article
Cite this article as:
Pande V., Sousa F. S. and Ramos J. M., Direct Covalent Modification as a Strategy to Inhibit Nuclear Factor-Kappa B, Current Medicinal Chemistry 2009; 16 (32) . https://dx.doi.org/10.2174/092986709789578222
DOI https://dx.doi.org/10.2174/092986709789578222 |
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
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...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
- 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
-
Antibody Based Therapies in Acute Leukemia
Current Drug Targets The Role of Anti-Inflammatory Drugs in Respiratory Diseases - Pirfenidone, Penicillamine, Chloroquine and Chlorambucil
Current Respiratory Medicine Reviews Antibodies As Promising Novel Neuroprotective Agents in the Central Nervous System Injuries
Central Nervous System Agents in Medicinal Chemistry Reversal of Tumor Induced Dendritic Cell Paralysis: A Treatment Regimen Against Cancer
Current Immunology Reviews (Discontinued) A Role for Milk Proteins and their Peptides in Cancer Prevention
Current Pharmaceutical Design Target Based Drug Design - A Reality in Virtual Sphere
Current Medicinal Chemistry Kinase Inhibitors in Multitargeted Cancer Therapy
Current Medicinal Chemistry Anti-Cancer Phytometabolites Targeting Cancer Stem Cells
Current Genomics Nilotinib Therapy in Chronic Myelogenous Leukemia: The Strength of High Selectivity on BCR/ABL
Current Drug Targets Nutrition, Nitrogen Requirements, Exercise and Chemotherapy-Induced Toxicity in Cancer Patients. A puzzle of Contrasting Truths?
Anti-Cancer Agents in Medicinal Chemistry Non-Transferrin Bound Iron - Determination in Biological Material and Clinical Implications
Current Pharmaceutical Analysis Natural Anticoagulant Proteins in the Regulation of Autoimmunity: Potential Role of Protein S
Current Pharmaceutical Design Gene Silencing in the Development of Personalized Cancer Treatment: The Targets, the Agents and the Delivery Systems
Current Gene Therapy Multi-Target Profile of Oleocanthal, An Extra-Virgin Olive Oil Component
Current Bioactive Compounds Comparison of Luminescence ADP Production Assay and Radiometric Scintillation Proximity Assay for Cdc7 Kinase
Combinatorial Chemistry & High Throughput Screening Molecular Imaging Kits for Hexosamine Biosynthetic Pathway in Oncology
Current Medicinal Chemistry The Role of Stem Cell Factor and Granulocyte-Colony Stimulating Factor in Treatment of Stroke
Recent Patents on CNS Drug Discovery (Discontinued) Benzothiazole: A Versatile and Multitargeted Pharmacophore in the Field of Medicinal Chemistry
Letters in Organic Chemistry Development ofNovel Compounds to Treat Autoimmune and Inflammatory Diseases and Graft Versus Host Reactions
Endocrine, Metabolic & Immune Disorders - Drug Targets HPV Pathway Profiling: HPV Related Cervical Dysplasia and Carcinoma Studies
Current Pharmaceutical Design