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Bioconjug Chem. 2011 Apr 20;22(4):529-32. doi: 10.1021/bc100477g. Epub 2011 Mar 9.

Glycated AAV vectors: chemical redirection of viral tissue tropism.

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1
Gene Therapy Center, Thurston-Bowles Building CB7352, University of North Carolina, Chapel Hill, NC 27599-7352, USA.

Abstract

A chemical approach for selective masking of arginine residues on viral capsids featuring an exogenous glycation reaction has been developed. Reaction of adeno-associated viral (AAV) capsids with the α-dicarbonyl compound, methylglyoxal, resulted in formation of arginine adducts. Specifically, surface-exposed guanidinium side chains were modified into charge neutral hydroimidazolones, thereby disrupting a continuous cluster of basic amino acid residues implicated in heparan sulfate binding. Consequent loss in heparin binding ability and decrease in infectivity were observed. Strikingly, glycated AAV retained the ability to infect neurons in the mouse brain and were redirected from liver to skeletal and cardiac muscle following systemic administration in mice. Further, glycated AAV displayed altered antigenicity demonstrating the potential for evading antibody neutralization. Generation of unnatural amino acid side chains through capsid glycation might serve as an orthogonal strategy to engineer AAV vectors displaying novel tissue tropisms for gene therapy applications.

PMID:
21388193
PMCID:
PMC3089942
DOI:
10.1021/bc100477g
[Indexed for MEDLINE]
Free PMC Article

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