Glycated AAV vectors: chemical redirection of viral tissue tropism
Open accessAbstract
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.
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Glycation on arginine and lysine residues decreased binding affinity to antibodies by 2 fold, but transduction efficiency was reduced by 1,000 fold in vitro, potentially due to disruption of AAV binding to heparin sulfate.
“Another study using glycation on arginine and lysine residues showed that although binding af fi nity to antibodies decreased by 2 fold, transduction ef fi ciency was reduced by 1,000 fold in vitro , potentially due to the disruption of AAV binding to heparin sulfate (136).”
From A versatile toolkit for overcoming AAV immunity (2022) · cites this paper as [136]
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- Authors
- Horowitz, E. D., Weinberg, M. S., & Asokan, A.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Gene Therapy Center
- Corresponding author
- Asokan, Aravind
- Venue
- Bioconjugate Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2011-03-09
- Volume
- 22
- Issue
- 4
- Pages
- 529-532
- ISSN
- 1043-1802 (ISSN-L)
- 1520-4812
- PMC
- PMC3089942
- OpenAlex
- W1993424127
- Cited by
- 40
- References
- 23
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 3 · 2020: 3 · 2019: 4 · 2018: 3 · 2016: 2 · 2015: 3 · 2014: 1
- FWCI
- 0.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Bioconjugate Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL089221-S2, R01HL089221)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- adeno-associated virus vectors, methylglyoxal, arginine modification, hydroimidazolone, heparan sulfate binding, tissue tropism, neuronal infection, unnatural amino acids, gene therapy vectors
- MeSH terms
- Adenoviridae, Animals, Genetic Vectors, Glycosylation, Models, Molecular, Genetic Therapy, Mice, Viral Tropism
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