A Highly Bioactive Lys-Deficient IFN Leads to a Site-Specific Di-PEGylated IFN with Equivalent Bioactivity to That of Unmodified IFN-α2b

Takashi Imada, Koji Moriya, Masahiko Uchiyama, Naoto Inukai, Mitsuhiro Hitotsuyanagi, Akiko Masuda, Takehiro Suzuki, Shotaro Ayukawa, Yo Ichi Tagawa, Naoshi Dohmae, Michinori Kohara, Masayuki Yamamura, Daisuke Kiga

研究成果: Article

抜粋

Although conjugation with polyethylene glycol (PEGylation) improves the pharmacokinetics of therapeutic proteins, it drastically decreases their bioactivity. Site-specific PEGylation counters the reduction in bioactivity, but developing PEGylated proteins with equivalent bioactivity to that of their unmodified counterparts remains challenging. This study aimed to generate PEGylated proteins with equivalent bioactivity to that of unmodified counterparts. Using interferon (IFN) as a model protein, a highly bioactive Lys-deficient protein variant generated using our unique directed evolution methods enables the design of a site-specific di-PEGylated protein. Antiviral activity of our di-PEGylated IFN was similar to that of unmodified IFN-α2b. The di-PEGylated IFN exhibited 3.0-fold greater antiviral activity than that of a commercial PEGylated IFN. Moreover, our di-PEGylated IFN showed higher in vitro and in vivo stability than those of unmodified IFN-α2b. Hence, we propose that highly bioactive Lys-deficient proteins solve the limitation of conventional PEGylation with respect to the reduction in bioactivity of PEGylated proteins.

元の言語English
ページ(範囲)2537-2546
ページ数10
ジャーナルACS Synthetic Biology
7
発行部数11
DOI
出版物ステータスPublished - 2018 11 16

ASJC Scopus subject areas

  • Biomedical Engineering
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

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    Imada, T., Moriya, K., Uchiyama, M., Inukai, N., Hitotsuyanagi, M., Masuda, A., Suzuki, T., Ayukawa, S., Tagawa, Y. I., Dohmae, N., Kohara, M., Yamamura, M., & Kiga, D. (2018). A Highly Bioactive Lys-Deficient IFN Leads to a Site-Specific Di-PEGylated IFN with Equivalent Bioactivity to That of Unmodified IFN-α2b. ACS Synthetic Biology, 7(11), 2537-2546. https://doi.org/10.1021/acssynbio.8b00188