Creation of interferon-alpha8 mutants with amino acid substitutions against interferon-alpha receptor-2 binding sites using phage display system and evaluation of their biologic properties - PubMed (original) (raw)

doi: 10.1089/jir.2008.0038.

Madoka Taniai, Kakuji Torigoe, Shigeto Yamamoto, Norie Arai, Yasuo Suemoto, Kenshi Yoshida, Takanori Okura, Tetsuya Mori, Noboru Fujioka, Tadao Tanimoto, Manabu Miyata, Harumi Ariyasu, Chie Ushio, Mitsukiyo Fujii, Toshio Ariyasu, Masao Ikeda, Tsunetaka Ohta, Masashi Kurimoto, Shigeharu Fukuda

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Creation of interferon-alpha8 mutants with amino acid substitutions against interferon-alpha receptor-2 binding sites using phage display system and evaluation of their biologic properties

Kouzo Yamamoto et al. J Interferon Cytokine Res. 2009 Mar.

Abstract

In this study, we describe the creation of three interferon-alpha (IFN-alpha)8 mutants with markedly higher antiviral and antiproliferative activities in comparison with those of the wild-type (wt)IFN-alpha8, wtIFN-alpha2, and IFN-con1 using a phage display system. Sequence analysis showed that three out of the six hot-spot amino acid residues of wtIFN-alpha8 known to be important for the interaction with the IFN-alpha receptor-2 (IFNAR-2)-binding sites were substituted to other amino acids and the others remained. Although affinity analysis revealed that the dissociation constant (K(D)) of IFN-alpha8 mutants was almost the same with that of wtIFN-alpha8, furthermore, the rates of association (k(a)) and dissociation (k(d)) were relatively lower. These results suggest that changes in the surface electronic charge of amino acid residues lead to changes in binding affinity and kinetics (prolonged dissociation time) toward the IFNAR-2, resulting in the modification of the biological activity. Moreover, our results demonstrate that the molecular engineering of the IFN-alpha8 provides important insight into action of IFN and also it would be useful in the development of therapeutically prominent IFN preparations than those used in clinical practice.

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