The "sneaking-ligand" approach: cell-type specific inhibition of the classical NF-κB pathway

Methods in Molecular Biology
Bettina SehnertReinhard E Voll

Abstract

The intracellular delivery of molecules across the plasma membrane represents a major obstacle. The conjugation of cell-permeable peptides (CPPs) to proteins promotes the uptake and internalization. However, uptake of CPPs is receptor independent and not cell-type specific. Recently, we established the "sneaking-ligand" approach which is based on multimodular recombinant fusion proteins that consist of three modules connected with serine-glycine linkers. Module one is responsible for receptor-mediated endocytosis; module two supports translocation into the cytoplasm so that the effector module three can interact with its binding partner in the cytoplasm. For NF-κB inhibition, we described an NF-κB inhibitor that targets selectively the activated endothelium via an oligopeptide motif. Upon E-selectin-mediated endocytosis, the Pseudomonas exotoxin A domain II (ETAII) translocates the NEMO-binding peptide to the cytoplasm interfering with IκB kinase complex assembly. Inflammatory autoimmune diseases are triggered, but also resolved by a variety of cell types. Therefore, the inhibition of NF-κB should be restricted to those cells that are crucially involved in the pathogenesis of inflammatory diseases. A general blockade of NF-κB m...Continue Reading

Citations

Sep 9, 2017·The Journal of Experimental Medicine·Matthias KollekMiriam Erlacher
Apr 18, 2020·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Congcong ZhangAndrea L J Marschall
Feb 6, 2020·Journal of Medicinal Chemistry·Chiara BorsariMaria P Costi

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