Abstract
Deregulated NF-k activation is not only involved in cancer but also contributes to the pathogenesis of chronic inflammatory diseases like rheumatoid arthritis (RA) and multiple sclerosis (MS). Ideally, therapeutic NF-KappaB inhibition should only take place in those cell types that are involved in disease pathogenesis to maintain physiological cell functions in all other cells. In contrast, unselective NF-kappaB inhibition in all cells results in multiple adverse effects, a major hindrance in drug development. Hitherto, various substances exist to inhibit different steps of NF-kappaB signaling. However, powerful tools for cell-type specific NF-kappaB inhibition are not yet established. Here, we review the role of NF-kappaB in inflammatory diseases, current strategies for drug delivery and NF-kappaB inhibition and point out the “sneaking ligand” approach. Sneaking ligand fusion proteins (SLFPs) are recombinant proteins with modular architecture consisting of three domains. The prototype SLC1 binds specifically to the activated endothelium and blocks canonical NF-kappaB activation. In vivo, SLC1 attenuated clinical and histological signs of experimental arthritides. The SLFP architecture allows an easy exchange of binding and effector domains and represents an attractive approach to study disease-relevant biological targets in a broad range of diseases. In vivo, SLFP treatment might increase therapeutic efficacy while minimizing adverse effects.
Highlights
The nuclear transcription factor-kappaB (NF-kappaB) is known for its crucial role during immune and inflammatory responses, cell growth, survival and development [1,2,3]
NF-kappaB inhibitors may cause serious adverse events especially those associated with severe immunosuppression [18,19]
Inhibition strategies, the SL-approach has the advantage that it combines the strong therapeutic potential of blocking a crucial transcriptional activator of inflammation with a risk reduction achieved by restricting NF-kappaB blockade in a cell-type specific and activation state dependent manner
Summary
The nuclear transcription factor-kappaB (NF-kappaB) is known for its crucial role during immune and inflammatory responses, cell growth, survival and development [1,2,3]. An ubiquitous pharmacologic NF-kappaB inhibition in every cell type might increase the risk. To dampen NF-kappaB activity in a cell type-specific manner and to reduce adverse effects in clinical applications, pioneering approaches must be developed. This review provides an overview on the role of NF-kappaB in inflammatory diseases, on general strategies for drug delivery and NF-kappaB inhibition with a focus on the “sneaking ligand” (SL) approach as a promising strategy to improve the benefit risk ratio of a therapeutic targeting of the NF-kappaB pathway. The sneaking ligand approach represents a tool for cell-type specific targeting of signaling pathways and has been demonstrated to be applicable for a selective NF-kappaB inhibition in the cytokine-activated endothelium [23]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
