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Issue 45, 2018

Zwitterlation mitigates protein bioactivity loss in vitro over PEGylation

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Abstract

Conjugation with poly(ethylene glycol) (PEG) or PEGylation is a widely used tool to overcome the shortcomings of native proteins, such as poor stability, inadequate pharmacokinetic (PK) profiles, and immunogenicity. However, PEGylation is often accompanied by an unwanted detrimental effect on bioactivity, particularly, resulting from the amphiphilic nature of PEG. This is especially true for PEGylated proteins with large binding targets. Pegasys, a PEGylated interferon alpha-2a (IFN-α2a) bearing a 40 kDa branched PEG, is a typical example that displays only 7% in vitro activity of the unmodified IFN-α2a. In this work, by employing IFN-α2a as a model protein, we demonstrated that a protein conjugated with zwitterionic polymers (or zwitterlation) could significantly mitigate the antiproliferative bioactivity loss in vitro after polymer conjugation. The retained antiproliferative activity of zwitterlated IFN-α2a is 4.4-fold higher than that of the PEGylated IFN-α2a with the same polymer molecular weight, or 3-fold higher than that of the PEGylated IFN-α2a with a similar hydrodynamic size. It is hypothesized that nonspecific interactions between zwitterionic polymers and IFN-α2a/IFN-α2a receptors can be mitigated due to the super-hydrophilic nature of zwitterionic polymers. This, in turn, reduces the ‘nonspecific blocking’ between IFN-α2a and IFN-α2a receptors. In addition, we demonstrated that zwitterlated IFN-α2a showed a prolonged circulation time and a mitigated accelerated blood clearance after repeated injections in rats.

Graphical abstract: Zwitterlation mitigates protein bioactivity loss in vitro over PEGylation

Supplementary files

Article information


Submitted
19 Apr 2018
Accepted
13 Sep 2018
First published
14 Sep 2018

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2018,9, 8561-8566
Article type
Edge Article

Zwitterlation mitigates protein bioactivity loss in vitro over PEGylation

Y. Han, Z. Yuan, P. Zhang and S. Jiang, Chem. Sci., 2018, 9, 8561 DOI: 10.1039/C8SC01777H

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