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Published on: January 18, 2017
Direct covalent modification as a strategy to inhibit nuclear factor-kappa B
Vineet Pande1, Sérgio F Sousa, Maria João Ramos
1Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal.
Current Medicinal Chemistry
|September 17, 2009
Summary
Nuclear Factor-kappaB (NF-kappaB) is a key transcription factor implicated in diseases like cancer and inflammation. This review explores novel covalent inhibitors targeting NF-kappaB
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Nuclear Factor-kappaB (NF-kappaB) is a crucial transcription factor involved in cellular responses.
- Dysregulated NF-kappaB activation is linked to various pathologies, including cancer, inflammation, neurodegeneration, and AIDS.
- Targeting NF-kappaB for therapeutic inhibition is a significant focus in pharmaceutical research.
Purpose of the Study:
- To critically review pharmacological agents that inhibit NF-kappaB through covalent modification.
- To explore the role of redox-regulation in NF-kappaB activation and DNA binding.
- To discuss the potential of developing a new class of NF-kappaB inhibitors via covalent modification.
Main Methods:
- Review of existing literature on NF-kappaB pathway and its inhibitors.
- Analysis of covalent modification strategies targeting redox-sensitive cysteine residues in NF-kappaB subunits.
- Discussion of biochemical events like S-thiolation, S-nitrosylation, and irreversible covalent modification.
Main Results:
- NF-kappaB activation involves cytoplasmic sequestration and release of p50/p65 subunits upon IkappaB degradation.
- Covalent modification of redox-regulated cysteine residues offers a direct approach to inhibit NF-kappaB DNA binding.
- Alkylating agents represent a primary class of studied covalent NF-kappaB inhibitors.
Conclusions:
- Covalent modification of NF-kappaB presents a promising strategy for therapeutic intervention.
- Understanding redox-regulation provides a basis for designing novel NF-kappaB inhibitors.
- This approach holds potential for developing a new class of drugs targeting NF-kappaB-mediated diseases.
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