Biochemistry (Moscow)

, Volume 75, Issue 12, pp 1458–1463

Novel mutants of human tumor necrosis factor with dominant-negative properties

Authors

    • Shemyakin-Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of Sciences
  • E. F. Boldyreva
    • Shemyakin-Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of Sciences
  • S. A. Yakimov
    • Shemyakin-Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of Sciences
  • S. V. Guryanova
    • Shemyakin-Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of Sciences
  • D. A. Dolgikh
    • Shemyakin-Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of Sciences
    • Biological FacultyLomonosov Moscow State University
  • S. A. Nedospasov
    • Biological FacultyLomonosov Moscow State University
    • Engelhardt Institute of Molecular BiologyRussian Academy of Sciences
  • M. P. Kirpichnikov
    • Shemyakin-Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of Sciences
    • Biological FacultyLomonosov Moscow State University
Article

DOI: 10.1134/S0006297910120060

Cite this article as:
Shingarova, L.N., Boldyreva, E.F., Yakimov, S.A. et al. Biochemistry Moscow (2010) 75: 1458. doi:10.1134/S0006297910120060

Abstract

Tumor necrosis factor (TNF) is a polyfunctional cytokine, one of the key mediators of inflammation and innate immunity. On the other hand, systemic or local TNF overexpression is typical of such pathological states as rheumatoid arthritis, psoriasis, Crohn’s disease, septic shock, and multiple sclerosis. Neutralization of TNF activity has a marked curative effect for some diseases; therefore, the search for various TNF blockers is a promising field of protein engineering and biotechnology. According to the previously developed concept concerning the possibility of designing dominant-negative mutants, the following TNF variants have been studied: TNFY87H + A145R, TNFY87H + A96S + A145R, and TNFV91N + A145R. All of these form inactive TNF heterotrimers with the native protein. The ability of mutants to neutralize the effect of TNF was investigated. The addition of mutants to the native protein was shown to provide a concentration-dependent suppression of TNF cytotoxicity against the mouse fibroblast cell line L929. Thus, novel inhibitors of human TNF can be engineered on the basis of these muteins.

Key words

tumor necrosis factor (TNF)mutantsTNF inhibitors

Abbreviations

DN-TNF

dominant-negative TNF inhibitors

TNF

tumor necrosis factor

TNFRI and TNFRII

TNF receptors

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© Pleiades Publishing, Ltd. 2010