Novel mutants of human tumor necrosis factor with dominant-negative properties |
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Authors: | L N Shingarova E F Boldyreva S A Yakimov S V Guryanova D A Dolgikh S A Nedospasov M P Kirpichnikov |
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Institution: | Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia. lshing@mx.ibch.ru |
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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. |
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