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Microbial Membrane-Permeating Peptides and Their Applications 381 α-helical linear peptides LL-37 LLGDFFRKSKEKIGKE<strong>FK</strong>RIVQRIKDFLRNLVPRTES Cecropin P1 SWLSKTAKKLENSAKKRISEGIAIAIQGGPR Peptides containing disulfide bonds aα-defensins ACYCRIPACIAGERRYGTCIYQGRLWAFCC ?β -defensin DHYNCVSSGGQCLYSACPIFTKIQGTCYRGKAKCCK � � � � bactenecin RLCRIVVIRVCR Peptides with one or two dominating amino acids PR-39 RRRPRPPYLPRPRPPPFFPPRLPPRIPPGFPPRFPPRFPGKR-NH2 Indolicidin ILPWKWPWWPWRR-NH2 cp � � � � � � � � cp � � (a) Animal cell membrane Bacterial cell membrane (b) Cholestrol Zwitterionic lipid Negatively charged lipid FIGURE 18.2 Structural classes of cell-permeating cationic antimicrobial peptides. (a) structural classes of natural antimicrobial peptides; (b) proposed basis for cell-type specific interaction based on cell surface charge differences between microbial and host cells. predominance of one or two amino acids (usually R, P, W, G, or H) and loop peptides with just one disulfide bond. In all cases, however, it is clear that a minimum size is required to maintain antimicrobial activity, approximately that needed to span a lipid bilayer (around 12 amino acids). The membrane-disturbing activity of larger peptides and proteins (>40 amino acids) is usually confined to subdomains. Linear peptides are susceptible to enzymatic degradation; microbial resistance to antimicrobial peptides can be provided by up-regulation of membrane-associated proteases. 20 Clearly, protease stability is an important feature that appears to be improved in natural antimicrobial peptides by the presence of disulfide bonds. For
382 Cell-Penetrating Peptides: Processes and Applications example, the recently discovered theta-defensin from Rhesus macaque is a macrocyclic peptide with three disulfide bonds and a structure similar to protegrin from pig. 21 The same motif is also found in macrocyclic peptides from plants, although the cross-linking arrangement of disulfide bonds differs. 22 Interestingly, another macrocylic peptide AS-48, a plasmid-encoded peptide ex<strong>press</strong>ed by Enterococcus faecalis, shows remarkable structural similarities with porcine NK-lysin in terms of size and α-helical fold. 23 Therefore, among natural antimicrobial peptides, a range of structural arrangements can provide stable and active peptides. When designing antimicrobial peptides, another strategy is to incorporate nonnatural amino acids. For example, peptides containing D-amino acids can display improved antimicrobial activities because they retain their activity but are more resistant to proteases. 24-26 In our studies (Andersson et al., unpublished), we have noticed that Mycobacterium smegmatis is insensitive to certain α-helical peptides, while the corresponding D-forms have higher activities. Furthermore, it is possible to synthesize short cyclic amphiphilic peptides with both L- and D-amino acids, and these modified circular peptides display good protease resistance. 27 18.3 MECHANISMS OF ACTION 18.3.1 CELL UPTAKE 18.3.1.1 Cell Permeation by Cationic Peptides In broad terms, microbial cell permeation by peptides can be seen as a three-step process. The first event is an electrostatic attraction of the peptide to the membrane surface (Figure 18.2b). The second involves membrane disruption and penetration and, possibly, some reorganization of the peptide structure. As peptides accumulate at the surface and start to displace lipids, this would eventually lead to local disruptions of the membrane (“carpet model”) or perhaps formation of transient peptidelipid “wormhole” pores. 28-30 Such disorganization or pore formation could allow cellular components to leak out and weaken the bacterial wall, creating opportunities for peptides to translocate into the inner membrane and subsequently into the cytoplasm. It also seems possible for peptides to translocate without causing significant membrane disruption. 31,32 Finally, in the third step the peptide passes the membrane and gains access to intracellular processes. In a more specific example, cationic peptide uptake into Gram-negative bacteria can be seen as a “self promoted” process, reflecting the fact that uptake is receptor independent. 5 According to this view, cationic peptides would contact the outer membrane through electrostatic attraction between positively charged antimicrobial peptides and negatively charged membrane lipids and the LPS layer. At this point peptides could compete for divalent cation binding sites within the outer cell membrane. In Escherichia coli, such competition would disrupt stabilizing cross-linking between LPS molecules and therefore reduce outer membrane integrity, which would provide opportunities for peptides to enter the membrane. The membrane charge gradient (inside negative) would then force cationic peptides into cells.
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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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Model Amphipathic Peptides 91 16. H
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Signal Sequence-Based Cell-Penetrat
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116 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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Page 370 and 371: Cell-Penetrating Peptides as Vector
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Page 400 and 401: Microbial Membrane-Permeating Pepti
Page 418 and 419: Index A Abaecin, 129 Abz radiolabel
Page 420 and 421: Index 399 Diffraction, 168 Disulphi
Page 422 and 423: Index 401 structure prediction, 187
Page 424 and 425: Index 403 pRB proteins, Tat-E1A bin
Page 426 and 427: Index 405 lipid perturbation (secon
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