Adenovirus targeting to prostate-specific membrane antigen through virus-displayed, semirandom peptide library screening.
The convergence of phage-displayed peptide libraries and recombinant viral vectors launched a promising new direction in targeted viral gene therapeutics, but the translation of targeting peptides to functional cancer therapeutic agents has been challenging. Here, we report progress in developing a successful strategy to optimize targeted viral infection through adenovirus-displayed, semirandom peptide libraries. A phage-derived peptide targeting the prostate-specific membrane antigen (PSMA) was genetically incorporated into the adenoviral capsid Fiber protein and flanked by random peptide cassettes. The resulting adenovirus library was biopanned against PSMA-expressing cells and tumors to identify a PSMA-retargeted adenovirus. While the initial peptide alone could not target viral infection, the selected virus preferentially infects PSMA-expressing cells through the targeting peptide and infects LNCaP tumors after intravenous injection. Our results indicate that virus-displayed, semirandom peptide libraries can be used to optimize targeting infection. This approach represents a novel principle for developing targeted agents in a variety of disease models.
Wu
Ping
P
The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Kudrolli
Tarana A
TA
Chowdhury
Wasim H
WH
Liu
Minzhi M
MM
Rodriguez
Ronald
R
Lupold
Shawn E
SE
D000256:Adenoviridae / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D001483:Base Sequence; D036022:Capsid Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007275:Injections, Intravenous; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements / Q000379:methods; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D019151:Peptide Library; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D014183:Transplantation, Heterologous
D000954:Antigens, Surface; D036022:Capsid Proteins; D009842:Oligopeptides; D019151:Peptide Library; C018315:hexon capsid protein, Adenovirus; D008156:Luciferases; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II