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Hum Gene Ther. 1999 Nov 1;10(16):2577-86.

Enhancement of adenovirus-mediated gene delivery by use of an oligopeptide with dual binding specificity.

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1
Laboratoire de Virologie et Pathogénèse Virale, CNRS UMR-5537, Faculté de Médecine R.T.H. Laennec, Lyon, France.

Abstract

The efficiency of human adenovirus serotype 5 (Ad5) transgene delivery was tested on several human and animal cell lines in vitro, by using a bimodular 35-mer oligopeptide carrying two peptide domains with different ligand specificities. One domain mimicked the fiber knob-binding region of the alpha2 domain of human MHC-1 molecules (MH20), and the other corresponded to the gastrin-releasing peptide (GRP). Two synthetic peptides with different configurations were analyzed in Ad-mediated gene transfer assays using Ad5Luc3 vector carrying the luciferase reporter gene. One peptide (GRP-MH20) had the GRP domain on the N-terminal side of MH20, while the other (MH20-GRP), the C-terminally amidified GRP, was on the C-terminal side of MH20. The GRP-MH20 peptide, but not MH20-GRP, was capable of enhancing luciferase gene delivery to Ad-susceptible cells in a GRP receptor-dependent manner. More importantly, GRP-MH20 could also confer susceptibility to Ad infection to normal or cancer cells that lack fiber receptors for the virus. Our data suggested that GRP receptors could function efficiently as alternative attachment receptors for Ad5, but that Ad5 bound to GRP receptors still depended, at least partially, on the penton base-mediated endocytotic pathway for subsequent cell entry. Gene delivery by a human adenovirus serotype 5 (Ad5) vector was assayed with a bimodular oligopeptide carrying two peptide domains of different binding specificities. One domain was a high-affinity peptide ligand of the Ad5 fiber knob (MH20), and the other corresponded to the gastrin-releasing peptide (GRP). The synthetic peptide GRP-MH20 was found to be capable of enhancing Ad-mediated gene transfer to Ad-susceptible cells in a GRP receptor-dependent manner. More importantly, GRP-MH20 could also confer susceptibility to Ad infection to normal or cancer cells that lack fiber receptors. Our data suggested that GRP receptors could function efficiently as alternative attachment receptors for Ad5, but virus bound to GRP receptors still depended partially on the penton base-mediated pathway for cell entry.

PMID:
10566886
DOI:
10.1089/10430349950016627
[Indexed for MEDLINE]

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