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Site-Specific PEGylated Adeno-Associated Viruses with Increased Serum Stability and Reduced Immunogenicity

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 100191 Beijing, China
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2017, 22(7), 1155;
Received: 16 June 2017 / Revised: 5 July 2017 / Accepted: 7 July 2017 / Published: 11 July 2017
PDF [2421 KB, uploaded 11 July 2017]


Adeno-associated virus (AAV) is one of the most extensively studied and utilized viral vectors in clinical gene transfer research. However, the serum instability and immunogenicity of AAV vectors significantly limit their application. Here, we endeavored to overcome these limitations by developing a straightforward approach for site-specific PEGylation of AAV via genetic code expansion. This technique includes incorporation of the azide moiety into the AAV capsid protein followed by orthogonal and stoichiometric conjugation of a variety of polyethylene glycols (PEGs) through click chemistry. Using this approach, only the chosen site(s) was consistently PEGylated under mild conditions, preventing nonselective conjugation. Upon a series of in vitro examinations, AAVs conjugated with 20-kD PEG at sites Q325+1, S452+1, and R585+1 showed a 1.7- to 2.4-fold stability improvement in pooled human serum and a nearly twofold reduction in antibody recognition. Subsequent animal research on Sprague Dawley rats displayed a promising 20% reduction in antibody inducement and a higher virus titer in the blood. Together, our data demonstrate successful protection of an AAV vector from antibody neutralization and blood clearance, thereby increasing the efficiency of therapeutic gene delivery. View Full-Text
Keywords: adeno-associated virus 2; PEGylation; genetic code expansion; selective conjugation adeno-associated virus 2; PEGylation; genetic code expansion; selective conjugation

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Yao, T.; Zhou, X.; Zhang, C.; Yu, X.; Tian, Z.; Zhang, L.; Zhou, D. Site-Specific PEGylated Adeno-Associated Viruses with Increased Serum Stability and Reduced Immunogenicity. Molecules 2017, 22, 1155.

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