Journal
ACTA BIOCHIMICA ET BIOPHYSICA SINICA
Volume 46, Issue 9, Pages 782-791Publisher
OXFORD UNIV PRESS
DOI: 10.1093/abbs/gmu068
Keywords
staphylokinase; site-specific pEGylation; immunogenicity; pharmacokinetic; fibrinolytic activity
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Funding
- Provincial Science and Technology Department of Hebei Province [09276418D-3]
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The bacterial plasminogen-activator staphylokinase (Sak) is a promising thrombolytic agent for treating acute myocardial infarction. To effectively reduce the immunogenicity of Sak while maintaining its fibrinolytic activity, site-specific PEGylation was performed in the present study. The chemoselective cysteine PEGylation site was selected within an immunodominant region (amino acid residues 71-87) using an in silico approach. The PEGylated Sak variants prepared in this study showed a purity of >97.0%. PEGylation at Position 80 resulted in a Sak variant Sak(E80C-PEG) which has similar fibrinolytic activity and thermostability compared with the native recombinant staphylokinase (r-Sak). The immunogenicity of Sak(E80C-PEG) in guinea pigs was greatly reduced compared with the native r-Sak. Furthermore, preliminary pharmacokinetic results suggested that the plasma clearance of Sak(E80C-PEG) from the blood stream of rabbit was significantly decreased compared with that of r-Sak, resulting in a 2.8-fold increase of initial half-life and a 3.8-fold increase of systemic availability. In summary, these results demonstrated that site-specific PEGylation yielded a novel Sak variant Sak(E80C-PEG) with remarkable advantages over the unmodified Sak.
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