Computational Design of Variant TNF Molecules: A Novel Methodology for Inhibition of Proinflammatory Cascades

Edward Abraham^*

Roger Sherman Mitchell Professor of Pulmonary and Critical Care Medicine, Vice Chair, Administrative Affairs, 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, Tel: 303-315-7047, Fax: 303-315-5632

Summary: 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.

*Contact information. E-mail, Edward.Abraham{at}UCHSC.edu

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