Chemoselective attachment of small molecule effector functionality to human adenoviruses facilitates gene delivery to cancer cells.

We demonstrate here a novel two-step "click" labeling process in which adenoviral particles are first metabolically labeled during production with unnatural azido sugars. Subsequent chemoselective modification allows access to viruses decorated with a broad array of effector functionality. Adenoviruses modified with folate, a known cancer-targeting motif, demonstrated a marked increase in gene delivery to a murine cancer cell line.

[1]  Q. Wang,et al.  Surface Modification of Tobacco Mosaic Virus with “Click” Chemistry , 2008, Chembiochem : a European journal of chemical biology.

[2]  Carolyn R Bertozzi,et al.  Incorporation of azides into recombinant proteins for chemoselective modification by the Staudinger ligation , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[3]  T. Park,et al.  Folate immobilized and PEGylated adenovirus for retargeting to tumor cells. , 2006, Bioconjugate chemistry.

[4]  D. Curiel,et al.  Targeted and shielded adenovectors for cancer therapy , 2006, Cancer Immunology, Immunotherapy.

[5]  Jennifer A. Prescher,et al.  Imaging cell surface glycans with bioorthogonal chemical reporters. , 2007, Journal of the American Chemical Society.

[6]  David T. Curiel,et al.  Engineering targeted viral vectors for gene therapy , 2007, Nature Reviews Genetics.

[7]  D. Nowotnik,et al.  Vitamin-mediated targeting as a potential mechanism to increase drug uptake by tumours. , 2004, Journal of inorganic biochemistry.

[8]  M. Francis,et al.  Oxidative coupling of peptides to a virus capsid containing unnatural amino acids. , 2008, Chemical communications.

[9]  M. Finn,et al.  Analysis and optimization of copper-catalyzed azide-alkyne cycloaddition for bioconjugation. , 2009, Angewandte Chemie.

[10]  M. Barry,et al.  Characterization of human adenovirus serotypes 5, 6, 11, and 35 as anticancer agents. , 2009, Virology.

[11]  A. Rivera,et al.  Optimization of capsid-incorporated antigens for a novel adenovirus vaccine approach , 2008, Virology Journal.

[12]  J. Wilson,et al.  Development of a rapid method for the PEGylation of adenoviruses with enhanced transduction and improved stability under harsh storage conditions. , 2000, Human gene therapy.

[13]  P. Low,et al.  Folate-targeted therapeutic and imaging agents for cancer. , 2009, Current opinion in chemical biology.

[14]  Duane E. Prasuhn,et al.  Unnatural amino acid incorporation into virus-like particles. , 2008, Bioconjugate chemistry.

[15]  M. Finn,et al.  Accelerated bioorthogonal conjugation: a practical method for the ligation of diverse functional molecules to a polyvalent virus scaffold. , 2005, Bioconjugate chemistry.

[16]  G. Cauet,et al.  Identification of the glycosylation site of the adenovirus type 5 fiber protein. , 2005, Biochemistry.

[17]  Florian Kreppel,et al.  Modification of adenovirus gene transfer vectors with synthetic polymers: a scientific review and technical guide. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[18]  M. Magnusson,et al.  Adenovirus type 5 fiber knob domain has a critical role in fiber protein synthesis and encapsidation. , 2006, The Journal of general virology.

[19]  Jennifer A. Prescher,et al.  A comparative study of bioorthogonal reactions with azides. , 2006, ACS chemical biology.

[20]  C. Bertozzi,et al.  Chemical Approaches To Perturb, Profile, and Perceive Glycans , 2009, Accounts of chemical research.

[21]  R. Marchase,et al.  Relative accessibility of N-acetylglucosamine in trimers of the adenovirus types 2 and 5 fiber proteins , 1990, Journal of virology.

[22]  M. Finn,et al.  Virus-glycopolymer conjugates by copper(I) catalysis of atom transfer radical polymerization and azide-alkyne cycloaddition. , 2005, Chemical communications.

[23]  S. Kochanek,et al.  Adenoviral vectors for gene transfer and therapy , 2004, The journal of gene medicine.

[24]  D. Curiel,et al.  Transductional targeting of adenovirus vectors for gene therapy , 2006, Cancer Gene Therapy.

[25]  S. Kochanek,et al.  Combined genetic and chemical capsid modifications enable flexible and efficient de- and retargeting of adenovirus vectors. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[26]  C. Bertozzi,et al.  Cell surface engineering by a modified Staudinger reaction. , 2000, Science.

[27]  D. Curiel,et al.  Current issues and future directions of oncolytic adenoviruses. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[28]  M. Magnusson,et al.  Genetic retargeting of adenovirus vectors: functionality of targeting ligands and their influence on virus viability , 2002, The journal of gene medicine.

[29]  K. Überla,et al.  Replication Properties of Human Adenovirus In Vivo and in Cultures of Primary Cells from Different Animal Species , 2006, Journal of Virology.

[30]  Carolyn R Bertozzi,et al.  A chemical approach for identifying O-GlcNAc-modified proteins in cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.