Abstract
We report the identification of a new human tumor necrosis factor-alpha (TNF-α) specific peptide selected by competitive panning of a phage library. Competitive elution of phages was obtained using the monoclonal antibody adalimumab, which neutralizes pro-inflammatory processes caused by over-production of TNF-α in vivo, and is used to treat severe symptoms of rheumatoid arthritis. The selected peptide was synthesized in monomeric and branched form and analyzed for binding to TNF-α and competition with adalimumab and TNF-α receptors. Results of competition with TNF-α receptors in surface plasmon resonance and melanoma cells expressing both TNF receptors make the peptide a candidate compound for the development of a novel anti-TNF-α drug.
Highlights
Tumor necrosis factor-alpha (TNF-α) is a potent pro-inflammatory cytokine exerting pleiotropic effects on various cell types
For this selection the same phage library was injected over biotinylated hTNF-α, previously immobilized on a streptavidin (SA) sensor chip, and bound phages were eluted by competition with adalimumab monoclonal antibody
TNF-α is an attractive target for the development of anti-inflammatory drugs because it is an important mediator in the pathogenesis of several inflammatory diseases, including rheumatoid arthritis (RA), Crohns disease and ankylosing spondylitis
Summary
Tumor necrosis factor-alpha (TNF-α) is a potent pro-inflammatory cytokine exerting pleiotropic effects on various cell types. TNF-α elicits a wide variety of responses, including fever, synthesis of Molecules 2014, 19 acute-phase proteins, increased vascular permeability, T and B-cell activation and migration, cell proliferation and apoptosis [1,2,3]. TNF is translated as a 26 kDa type II transmembrane protein that assembles into homo-trimers displayed on the cell surface of macrophages, lymphocytes and other cell types [4,5]. TNF-α is involved in the acute inflammatory response to stimuli, such as infection or tissue injury, and plays a critical role in the pathogenesis of chronic inflammation and chronic inflammatory diseases, such as rheumatoid arthritis (RA) and Crohn’s disease [13]. Five anti-TNF-α agents (infliximab, etanercept, adalimumab, certolizumab pegol and golimumab) have been successfully introduced for the treatment of chronic inflammatory diseases. We report the selection of a novel anti-human TNF-α peptide from a phage library, its synthesis as a tetra-branched molecule and in vitro characterization of the branched peptide for inhibition of TNF-α binding to its receptors, which is the first property for an anti-TNF-α agent to be considered a potential drug for antiinflammatory therapies
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