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5 CONTENTS 0-8493-1141-1/02/$0.00+$1.50 © 2002 by CRC Press LLC Signal Sequence-Based Cell-Penetrating Peptides and Their Applications for Gene Delivery May C. Morris, Laurent Chaloin, Frédéric Heitz, and Gilles Divita 5.1 Introduction ....................................................................................................94 5.2 Signal Sequence: The Nuclear Localization Sequence.................................94 5.2.1 Introduction: The Nuclear Localization Sequence............................94 5.2.2 Mechanism of Nuclear Transport ......................................................95 5.2.3 NLS Involved in the Delivery of Active Cargo.................................97 5.3 NLS-Containing Cell-Penetrating Peptides...................................................99 5.3.1 Signal Sequence-Based Peptides: Import and Targeting Signals......99 5.3.2 Import Signal Sequences ...................................................................99 5.3.3 Applications for NLS in Cell-Penetrating Peptides ........................100 5.4 Utilization of the NLS Pathway for Nuclear Import of Gene Delivery Vectors ...........................................................................................102 5.4.1 Challenges in Gene Delivery...........................................................102 5.4.2 Noncovalent Incorporation of Nuclear Localization Sequences.....102 5.4.2.1 Covalent Linkage of NLS to Condensing Agents ...........104 5.4.2.2 NLS Linkage Directly to DNA ........................................104 5.5 Design and Evaluation of NLS-Containing Cell-Penetrating Peptides ......105 5.5.1 Mechanism of Cell Delivery............................................................105 5.5.2 Mechanism of Nuclear Transport ....................................................106 5.6 Conclusions ..................................................................................................108 References..............................................................................................................109 93
94 Cell-Penetrating Peptides: Processes and Applications 5.1 INTRODUCTION Over the past 10 years, substantial progress has been made in the development of cell-penetrating peptide-based drug delivery systems. This was directly correlated with the dramatic acceleration in the production of new therapeutic molecules because the cell delivery systems described until then were restricted by very specific issues. As such, the goal became to design short synthetic peptides which would incorporate cellular addresses and intramolecular routing signals and to formulate synthetic peptide cargo complexes which could overcome both extracellular and intracellular limitations. 1-5 Cell-penetrating peptides present several advantages in that they are modulable, lack immunogenicity, easy to produce, and can incorporate a number of specific attributes required for efficient cargo delivery. They have been shown efficiently to introduce drugs, antisense DNA, PNA, oligonucleotides, and small proteins into cells in vivo and in vitro. 4-9 In the design of cell-penetrating peptides, the two main barriers to overcome are the cell membrane and the nuclear membrane. Signal sequence-based cellpenetrating peptides described in the literature can be subdivided into two types: natural peptides and chimeric peptides. The main cell routing elements are termed import signals and nuclear localization sequences (NLSs) and are presumed to function in most eukaryotic cells. Efficient uptake into cells in the absence of specific receptors or transporters and escape from the endosomal or lysosomal compartments are additional obstacles to be surmounted and therefore key parameters to be considered in the rational design and engineering of cell-penetrating peptides. Although the nucleus represents a major barrier, it also constitutes one of the major targets for drug and gene therapy. Indeed, cell-penetrating peptides containing NLS have been extensively used for drug and cargo delivery, with the NLS either directly incorporated in the formulation or cross-linked to the cell-penetrating peptide or even to its cargo. 6-10 This chapter will highlight characteristics of NLS-based peptides designed to address the nucleus and will discuss why understanding the mechanism of nuclear import and of structural features of cell-penetrating peptides is essential for improvement of in vivo drug therapy. 5.2 SIGNAL SEQUENCE: THE NUCLEAR LOCALIZATION SEQUENCE 5.2.1 INTRODUCTION: THE NUCLEAR LOCALIZATION SEQUENCE Although the nucleus constitutes one of the major cellular compartments to be targeted, nuclear delivery of drugs and DNA is limited by the selectivity of the nuclear envelope. Indeed, in the case of gene therapy, for example, ex<strong>press</strong>ion of transcripts can only take place following delivery into the nucleus. However, transport of therapeutic DNA from the cytoplasm into the nucleus constitutes one of the major limiting steps in nondividing cells. Fortunately, over the last few years, the structure and molecular mechanisms of nuclear transport have been characterized in detail, thereby enabling more appropriate design of cell-penetrating peptides
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CELL- PENETRATING PEPTIDES Processe
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Pharmacology and Toxicology: Basic
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Library of Congress Cataloging-in-P
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to the handbook are prominent resea
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REFERENCES 1. Green, M. and Loewens
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Contributors Mats Andersson Microbi
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Erin T. Pelkey Department of Chemis
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Contents Section I Classes of Cell-
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Chapter 16 Cell-Penetrating Peptide
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The Tat-Derived Cell-Penetrating Pe
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24 Cell-Penetrating Peptides: Proce
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144 Cell-Penetrating Peptides: Proc
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Interactions of Cell-Penetrating Pe
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Structure Prediction of CPPs and It
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FIGURE 9.7 (Color Figure 9.7 follow
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FIGURE 9.8 The center of the figure
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Biophysical Studies of Cell-Penetra
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Toxicity and Side Effects of Cell-P
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Kinetics of Uptake of Cell-Penetrat
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Cell-Penetrating Peptide Conjugatio
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FIGURE 15.9 (Color Figure 15.9 foll
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Cell-Penetrating Peptides as Vector
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TABLE 16.1 Examples of Transport of
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CPP 2 Cargo or mRNA CAP Antisense A
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Microbial Membrane-Permeating Pepti
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Index A Abaecin, 129 Abz radiolabel
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Index 399 Diffraction, 168 Disulphi
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Index 401 structure prediction, 187
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Index 403 pRB proteins, Tat-E1A bin
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Index 405 lipid perturbation (secon
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