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 R GD which mediates binding to the integrin cell surface receptors alpha (n)u,beta(3) and alpha(n)u beta(5). These integrins then mediate adeno virus internalization. We have developed penton base chimeras that rec ognize tissue-specific integrin receptors for replacing the wild-type RGD peptide motif with alpha(n)u beta(3)- or alpha(4) beta(1)-specific peptide motifs. In one chimera the original haiRGDtta motif was repla ced with the peptide motif eiLDVpst which mediated chimera binding to the integrin alpha(4) beta(1). This integrin is expressed at high leve ls on lymphocytes and monocytes but is not expressed on epithelial or endothelial cells. In a second chimera the wild-type sequences flankin g the RGD motif were altered to abrogate its interaction with alpha(n) u beta(5) is expressed primarily on epithelial cells whereas the integ rin alpha(n)u beta(3) is normally expressed on endothelial cells. The integrin alpha(n)u beta(3) is also aberrantly expressed on certain met astatic melanomas and glioblastomas. A deletion mutant lacking the RGD sequence did not bind to any integrins. Such chimeras incorporated in to adenovirus virions may be useful in targeting specific tissues in a denovirus-mediated gene delivery.