Targeting of adenovirus penton base to new receptors through replacement of its RGD motif with other receptor-specific peptide motifs.
The adenovirus coat protein, penton base, contains the peptide motif RGD which mediates binding to the integrin cell surface receptors alpha v beta 3 and alpha v beta 5. These integrins then mediate adenovirus internalization. We have developed penton base chimeras that recognize tissue-specific integrin receptors by replacing the wild-type RGD peptide motif with alpha v beta 3- or alpha 4 beta 1-specific peptide motifs. In one chimera the original haiRGDtfa motif was replaced with the peptide motif eiLDVpst which mediated chimera binding to the integrin alpha 4 beta 1. This integrin is expressed at high levels on lymphocytes and monocytes but is not expressed on epithelial or endothelial cells. In a second chimera the wild-type sequences flanking the RGD motif were altered to abrogate its interaction with alpha v beta 5 while retaining its specificity for alpha v beta 3. The integrin alpha v beta 5 is expressed primarily on epithelial cells whereas the integrin alpha v beta 3 is normally expressed on endothelial cells. The integrin alpha v beta 3 is also aberrantly expressed on certain metastatic melanomas and glioblastomas. A deletion mutant lacking the RGD sequence did not bind to any integrins. Such chimeras incorporated into adenovirus virions may be useful in targeting specific tissues in adenovirus-mediated gene delivery.
Wickham
T J
TJ
GenVec Inc, Rockville, MD 20852, USA.
Carrion
M E
ME
Kovesdi
I
I
D000256:Adenoviridae / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002213:Capsid / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism*; D036022:Capsid Proteins; D003001:Cloning, Molecular; D017931:DNA Primers; D007313:Insecta; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009838:Oligodeoxyribonucleotides; D009842:Oligopeptides; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011991:Receptors, Virus / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D015183:Restriction Mapping; D017384:Sequence Deletion; D014162:Transfection
D036022:Capsid Proteins; D017931:DNA Primers; D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D009842:Oligopeptides; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; C085301:adenovirus receptor; C043322:penton protein, adenovirus; C047981:arginyl-glycyl-aspartic acid