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In clinical medicine the use of neutralizing antibodies has revolutionized the treatment of a number of diseases and improved the quality of like of thousands of patients. However the use of these antibodies is not with out problems, including the development of an immune response to the antibodies themselves. DNA aptamers may be an alternate approach to antibodies for targeting cytokines where cytokine expression is directly contributing to disease pathogenesis, In this study we report the development and characterization of DNA aptamers for the neutralization of Interferon-gamma (IFN-g). A DNA aptamer has been developed for human IFN-g as reported by Kimoto and co-workers (Kimoto et al. 453–57, 2013 Nature Biotechnology). DNA aptamers are small single strand molecules that have high affinities for their target proteins. Modifying the DNA aptamer, by the addition of a few non-natural hydrophobic bases as a fifth base, greatly increases the affinity to IFN-g (Kd = 38 pM). These modified aptamers demonstrate increased stability in binding to IFN-g in the presence of mouse or human serum and efficiently neutralize the ability of IFN-g to induce the phosphorylation of STAT1. Furthermore, they appear to act by directly binding to IFN-g and preventing the interaction of IFN-g with its cell surface receptor. Thus DNA aptamers offer the intriguing possibility of small molecule inhibitors of cytokine signaling as an alternative to the use of neutralizing antibodies.