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crc press - E-Lib FK UWKS

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6<br />

CONTENTS<br />

0-8493-1141-1/02/$0.00+$1.50<br />

© 2002 by CRC Press LLC<br />

Hydrophobic Membrane<br />

Translocating Sequence<br />

Peptides<br />

Kristen Sadler, Yao-Zhong Lin, and James P. Tam<br />

6.1 Introduction ..................................................................................................115<br />

6.2 Signal Hypothesis ........................................................................................116<br />

6.3 Hydrophobic Translocating Peptides Based on the Signal Sequence<br />

h-Region .......................................................................................................117<br />

6.3.1 Development of SN50 Peptide: kFGF MTS Linked<br />

to NF-κB NLS .................................................................................117<br />

6.3.2 Applications of SN50 Peptide .........................................................119<br />

6.3.3 kFGF MTS Aids in Translocation of Other Cargoes......................119<br />

6.3.4 Identification of Translocation Activity of Integrin β 3 h-Region....122<br />

6.4 Mechanism of MTS Membrane Translocation............................................122<br />

6.5 Methods for Attaching Cargo and Targeting Domains<br />

to Translocating Peptides.............................................................................124<br />

6.6 Cationic Translocating Peptides...................................................................127<br />

6.7 Arginine–Proline-Rich Peptides as Translocating Peptides ........................129<br />

6.8 Proline-Rich Peptides as Translocating Peptides ........................................130<br />

6.9 Future Perspectives of Cell-Permeant Peptide Technology ........................130<br />

References..............................................................................................................132<br />

6.1 INTRODUCTION<br />

Advances in genomics and proteomics have led to the design of a significant number<br />

of therapeutic and diagnostic agents that target intracellular molecules. However,<br />

the delivery of such agents to the cytoplasm and nucleus is impeded by the cell<br />

membrane which is intrinsically impermeable to most peptides, proteins, and nucleic<br />

acids. To overcome this barrier, invasive techniques such as microinjection, electroporation,<br />

and application of pore-forming reagents have been used to introduce<br />

biologically active tools such as antibodies, synthetic peptides, and peptidomimetics<br />

into cells. 1-5 However, by their very nature, each of these techniques compromises the<br />

structural and functional integrity of the living cell. Furthermore, these techniques,<br />

115

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