NF-kappa B in human disease: current inhibitors and prospects for de novo structure based design of inhibitors

• Type: Another Publication in an International Scientific Journal
• Date: 2005

Authors

Pande, V (Author) Other; Ramos, MJ (Author) FCUP

Journal

Title: Current Medicinal Chemistry

Vol. 12

Pages: 357-374

ISSN: 0929-8673

Publisher: Bentham Science

Indexing

ISI Web of Knowledge - 114 Citations

Scopus - 125 Citations

Scientific classification

FOS: Medical and Health sciences > Basic medicine

Other information

Authenticus ID: P-000-5GB

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 18