Computational design of variant TNF molecules: a novel methodology for inhibition of proinflammatory cascades.
Site-directed mutagenesis of tumor necrosis factor (TNF) based on prediction of the interaction of specific residues with TNF receptors generated dominant-negative constructs, in which single- or double-amino acid changes result in decreased receptor binding and cellular activation. These dominant-negatives not only provide a novel manner to block the proinflammatory effects of TNF, but also can be used as a tool to examine ligand-receptor interactions and their importance in signaling. Because these TNF mutant molecules are smaller than those used for conventional anti-TNF therapies, such as etanercept or infliximab, they are likely to achieve greater tissue concentrations and may provide enhanced therapeutic effect. However, the immunogenicity, as well as efficacy, of the dominant-negative TNF constructs must be more completely examined.
Abraham
Edward
E
Department of Medicine, Head, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Box C272, 4200 East Ninth Avenue, Denver, CO 80262, USA. Edward.Abraham@UCHSC.edu
D019295:Computational Biology / Q000379:methods*; D015195:Drug Design; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000517:prevention & control; D018836:Inflammation Mediators / Q000138:chemical synthesis*; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D020033:Protein Isoforms / Q000138:chemical synthesis; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000138:chemical synthesis* / Q000235:genetics
D018836:Inflammation Mediators; D020033:Protein Isoforms; D014409:Tumor Necrosis Factor-alpha