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7 CONTENTS 0-8493-1141-1/02/$0.00+$1.50 © 2002 by CRC Press LLC Arginine-Rich Molecular Transporters for Drugs: The Role of Backbone and Side Chain Variations on Cellular Uptake Jonathan B. Rothbard, Erik Kreider, Kanaka Pattabiraman, Erin T. Pelkey, Christopher L. VanDeusen, Lee Wright, Bryan L. Wylie, and Paul A. Wender Abstract..................................................................................................................142 7.1 Introduction ..................................................................................................142 7.2 Materials and Methods.................................................................................144 7.2.1 General .............................................................................................144 7.2.2 Peptide Synthesis .............................................................................144 7.2.3 Robotic Peptide Synthesis ...............................................................144 7.2.4 Peptoid Polyamine Synthesis...........................................................145 7.2.5 Perguanidinylation of Peptoid Polyamines......................................146 7.2.6 Molecular Modeling.........................................................................146 7.2.7 Cellular Uptake Assays....................................................................146 7.3 Results ..........................................................................................................147 7.3.1 Guanidino Peptoid Design and Cellular Uptake .............................147 7.3.2 Role of the Side Chain Conformational Freedom of Guanidino Peptoids in Cellular Uptake ......................................149 7.3.3 Role of the Backbone Conformational Freedom of Guanidino Peptide Transporters in Cellular Uptake...................150 7.4 Discussion ....................................................................................................156 References..............................................................................................................159 141
142 Cell-Penetrating Peptides: Processes and Applications ABSTRACT The goal of this review is to summarize previously published work on the design and biological activity of a family of guanidinium peptoid transporters that differ in the length of their side chains and to compare these results with a more recently designed family of transporters containing non-α-amino acids, i.e., variations along the backbone. The latter group of peptides differs by the spacing of the arginine subunits along the peptide backbone. When these analogs were assayed for cellular uptake, the most important feature was shown to be not the nature of the substituted amino acid, but rather the distance between each of the arginines. When results of the two studies were compared a very similar pattern was observed. By increasing the conformational freedom of either the side chains of the peptoids or the backbone of peptides by the addition of methylene units, a significant enhancement in the rate of cellular uptake of the transporter was seen. Even though the conformational flexibility of peptoids and peptides is very different, addition of methylenes in either the backbone or the side chain results in enhanced cellular uptake, arguing that the flexibility of the guanidine headgroups can be accomplished in either of these ways. Typically, the biological activity of most biological ligands, particularly those functioning as inhibitors, increases with conformational restriction as preorganization in the form of the bound conformer favors tighter binding. The enhanced activity associated with increased conformational mobility observed for molecular transporters is in agreement with a dynamic transport system in which turnover rather than tightness of binding is critical for function. 7.1 INTRODUCTION Biological barriers have evolved to prevent entry of xenobiotics into tissues and cells. However, these same barriers often limit or preclude uptake, and therefore the therapeutic benefit, of a variety of drugs. Consequently, most drugs must be restricted in physical properties to allow cellular and tissue uptake. This requirement greatly limits the universe of potential therapeutics to a very small number of compounds. The studies reviewed below were directed toward the goal of enhancing or enabling delivery of drugs through biological barriers by conjugation to transporter molecules. Oligomers of arginine composed of six or more amino acids, either alone or when covalently attached to a variety of small molecules, cross biological membranes very effectively by an as yet undefined mechanism. 1 The chirality of the amino acid subunits in the arginine oligomers does not affect transport activity. In addition, a variety of other nonpeptide, guanidine-rich molecular transporters that do not share the composition or the spacing of a peptide have been shown to exhibit transport into cells. The guanidine headgroup of arginine appears to be the key structural unit for cellular uptake. 1,2 The rate of uptake is dependent on both the concentration of the oligomers and their guanidine content, with a greater rate observed as the length of the peptide is increased up to approximately 15 residues. Oligomers beyond this length enter cells less effectively, precipitate serum proteins, and exhibit cellular cytotoxicity at high micromolar concentrations. Detailed kinetic analyses demonstrated that nonamers of arginine were significantly more effective at crossing biological membranes than
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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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3 Transportans Margus Pooga, Mattia
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Transportans 55 Indeed, galparan is
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Transportans 57 especially the endo
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Transportans 59 In the penetration
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Transportans 61 A 21-mer antisense
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Transportans 63 Commonly, the prote
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Transportans 65 antibiotin antibodi
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Transportans 67 For cross-linking o
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Transportans 69 and still retain ef
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Model Amphipathic Peptides 73 its D
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Model Amphipathic Peptides 75 pmol/
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TABLE 4.1 Internalization of Peptid
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TABLE 4.2 Internalization of Peptid
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Model Amphipathic Peptides 81 relat
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Model Amphipathic Peptides 87 A cat
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Model Amphipathic Peptides 89 At th
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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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264 Cell-Penetrating Peptides: Proc
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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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