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J Mol Biol. 2008 Jul 25;380(5):777-82. doi: 10.1016/j.jmb.2008.05.047. Epub 2008 May 29.

Organelle-targeted delivery of biological macromolecules using the protein transduction domain: potential applications for Peptide aptamer delivery into the nucleus.

Author information

1
Laboratory of Pharmaceutical Proteomics, National Institute of Biomedical Innovation, 7-6-8 Saito-Asagi, Ibaraki, Osaka 567-0085, Japan.

Abstract

Extensive effort is currently being expended on the innovative design and engineering of new molecular carrier systems for the organelle-targeted delivery of biological cargoes (e.g., peptide aptamers or biological proteins) as tools in cell biology and for developing novel therapeutic approaches. Although cell-permeable Tat peptides are useful carriers for delivering biological molecules into the cell, much internalized Tat-fused cargo is trapped within macropinosomes and thus not delivered into organelles. Here, we devised a novel intracellular targeting technique to deliver Tat-fused cargo into the nucleus using an endosome-disruptive peptide (hemagglutinin-2 subunit) and a nuclear localization signal peptide. We show for the first time that Tat-conjugated peptide aptamers can be selectively delivered to the nucleus by using combined hemagglutinin-2 subunit and nuclear localization signal peptides. This nuclear targeting technique resulted in marked enhancement of the cytostatic activity of a Tat-fused p53-derived peptide aptamer against human MDM2 (mouse double minute 2) that inhibits p53-MDM2 binding. Thus, our technique provides a unique methodology for the development of novel therapeutic approaches based on intracellular targeting.

PMID:
18571668
DOI:
10.1016/j.jmb.2008.05.047
[Indexed for MEDLINE]

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