Development of next generation of therapeutic IFN-α2b via genetic code expansion. (June 2015)

• Record Type: Journal Article
• Authors: Zhang, Bo; Xu, Huan; Chen, Jingxian; Zheng, Yongxiang; Wu, Yiming; Si, Longlong; Wu, Ling; Zhang, Chuanling; Xia, Gang; Zhang, Lihe; Zhou, Demin
• Is Part Of: Acta biomaterialia. Volume 19(2015)
• Page Start: 100
• Page End: 111
• Publication Date: 2015-06
• Subjects: Site-specific PEGylation -- Interferon-α2b -- Genetic code expansion -- Bio-orthogonal conjugation; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1016/j.actbio.2015.03.002
• Languages: English
• ISSNs: 1742-7061

Abstract

Graphical abstract: Abstract: With the aim to overcome the heterogeneity associated with marketed IFN-α2b PEGylates and optimize the size of the PEG moiety and the site of PEGylation, we develop a viable and facile platform through genetic code expansion for PEGylation of IFN-α2b at any chosen site(s). This approach includes site-specific incorporation of an azide-bearing amino acid into IFN-α2b followed by orthogonal and stoichiometric conjugation of a variety of PEGs via a copper-free click reaction. By this approach, only the chosen site(s) within IFN-α2b is consistently PEGylated under mild conditions, leading to a single and homogenous conjugate. Furthermore, it makes the structure–activity relationship study of IFN-α2b possible by which the opposite effects of PEGylation on the biological and pharmacological properties are optimized. Upon re-examination of the PEGylated IFN-α2b isomers carrying different sizes of PEG at different sites, we find mono-PEGylates at H34, A74 and E107 with a 20-, 10- and 10-kDa PEG moiety, respectively, have both higher biological activities and better PK profiles than others. These might represent the direction for development of the next generation of PEGylated IFN-α2b.