title: NF-kappaB in human disease: current inhibitors and prospects for de novo structure based design of inhibitors.
abstract: Nuclear-Factor kappa B (NF-kappaB) is an inducible transcription factor of the Rel family, sequestered in the cytoplasm by the IkappaB family of proteins. NF-kappaB exists in several dimeric forms, but the p50/p65 heterodimer is the predominant one. Activation of NF-kappaB by a range of physical, chemical, and biological stimuli leads to phosphorylation and proteasome dependent degradation of IkappaB, leading to the release of free NF-kappaB. This free NF-kappaB then binds to its target sites (kappaB sites in the DNA), to initiate transcription. This transcription has been known to be involved in a number of diseases including cancer, AIDS, and inflammatory disorders. The present article focuses on two important issues of current and future interest- firstly a review of the main human diseases which are initiated due to NF-kappaB mediated transcription is presented. Next, comprehensive information on the current inhibitors which are targeted to interfere with the NF-kappaB pathway is provided. This latter section presents a critical review on different types of latest inhibitors targeting the complex NF-kappaB pathway at several stages. The inhibitors developed till date and still under investigation, include mainly those which interfere with the activation of NF-kappaB. Based on the complexity of NF-kappaB activation, and the current knowledge of the structural biology of NF-kappaB-DNA binding, finally it is proposed that a better approach to inhibit NF-kappaB induced transcription exists. In this context, a perspective is presented in the end, proposing de novo design of inhibitors which directly interact with the DNA Binding region of the free NF-kappaB (p50 subunit), so as to generate more specific and selective leads of NF-kappaB-DNA binding.
authors.affiliation: REQUIMTE, Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal.
authors.forename: V
authors.initials: V
authors.lastname: Pande
authors.forename: M J
authors.initials: MJ
authors.lastname: Ramos
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D014158:Transcription, Genetic / Q000187:drug effects; D014777:Virus Diseases / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D000975:Antioxidants; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease