Molecular Design Of Cell-penetrating Peptides Against NF-κB P65 Subunit And Identifying Of Its Anti-inflammatory Function

NF-κB is an ubiquitous transcription factor, and one of cross-talk points of multiple signal transduction pathway.It plays a pivotal role in basic processes such as regulation of the immune response,inflammatory response,virus replication,cell proliferation and apoptosis.It can regulate transcription and expression of many genes such as cytokines,adhesion molecules,chemotaxins,acute phase response proteins and enzymes,which take part in inflammatory responses.Excess activation of NF-κB is associated with pathogenesis and processes of various acute and chronic inflammatory diseases such as autoimmune disease,allergy,rheumatoid arthritis,asthma,psoriasis,arterosclerosis,glomerulonephritis,graft rejection,enteronitis,cachexia,thyroid disease syndrome,gastritis associated with Helicobacterium pylori.Therefore,many experts have suggested recently that NF-κB may be a potential novel anti-inflammatory target.Theoretically,effectively antagonizing NF-κB activity is one of effective ways to relieve and/or treat those inflammatory diseases.NF-κB binding to DNA cis-element(κB motif) is specific in the activation processes of NF-κB pathway,which is requisite for NF-κB mediated transcription of target genes.The p50/p65 heterodimer is the classical member of NF-κB which is more abundant and potent binding withκB motif,and regulates the expression of more genes than other hetero- or homo-dimers.Therefore,This makes it convincing that inhibitors targeting the NF-κB directly,by interacting with it in a way as to prevent interactions between p50/p65 heterodimer andκB motif,should better and more specifically inhibit biological activity of NF-κB.Both p50 and p65 play an important role in processes of NF-κB recognizing and binding withκB motif,but because p50 lack activation domain,p50 may dimerize to be p50/p50 homodimer which can bind withκB motif,but can't activate transcription of target genes. On the contrary,the interaction between p50/p65 heterodimer andκB motif can be inhibited competitively by p50/p50 homodimer,which is negative feedback regulation on...