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Microbial Membrane-Permeating Peptides and Their Applications 379 Gram-negative bacteria Gram-positive bacteria lp pp cp Yeast Mammalian cells cp bp cy lps pps pg cm Cytoplasm mp βg chi pps cm Cytoplasm gl pl FIGURE 18.1 Microbial and mammalian cell barriers. The cell barriers of different types of cells are illustrated. LPS, lipopolysaccharide; PG, peptidoglycon; PL, phospholipid; GL, glycolipid; PPS, periplasmic space; CM, cytoplasmic membrane; BP, braun lipoprotein; LP, lipoprotein; CP, carrier protein; PP, pore protein; TA, teichoic acid; MP, mannoprotein; βG, beta-glucan; CHI, chitin. (See Figure 18.2 for details on lipid characteristics.) its environment; however, cell membranes are in fact semipermeable to small molecules. In addition, microbial cell bilayers are coated with an extracellular matrix that provides a largely inert structural framework and protective barrier. The composition of the bilayer and the extracellular matrix varies with cell type, and these differences are important to the activities and cell type-specificity of cell-permeating peptides. Figure 18.1 illustrates cell barriers associated with different cell types. The cell barriers of prokaryotic cells are multilayered structures that provide stringent protection against foreign substances in the cell’s environment. 12 In the case of Gram-positive bacteria, the cell barrier consists of a phospholipid bilayer covered by a thick peptidoglycan layer and an outer capsule that varies in thickness cp cp ta pg cm cm
380 Cell-Penetrating Peptides: Processes and Applications between species. In the case of Gram-negative bacteria, the cell barrier consists of two phospholipid bilayers, with the inner membrane surrounded by a peptidoglycan layer and the outer coated on the exterior by a lipopolysaccharide (LPS) layer (Figure 18.1). 13 The LPS layer provides Gram-negative bacteria with a particularly stringent sieve against foreign substances. The cell barrier of eukaryotic cells typically presents less of an obstacle to permeating peptides because the main structure is the phospholipid bilayer. Most mammalian cells have little additional coating as protection. In contrast, fungal plasma membranes are enriched in inositol phosphoceramides and a thick outer protective cell wall composed of β-1,3 glucan and β-1,6 glucans and chitin. 14 In some cases the fungal cell wall can amount to as much as 40% of the dry cell mass. Therefore, fungi are similar to bacteria in having thick and complex barriers against cell-permeating peptides and other foreign substances. 18.2.2 ORIGINS AND DISCOVERY OF MICROBIAL CELL-PERMEATING PEPTIDES Antimicrobial peptides were discovered as a group of small, cationic peptides, and it was soon found that these peptides possessed potent bactericidal and fungicidal properties. 15-17 Antimicrobial peptides have been isolated from most vertebrate and invertebrate material studied, such as the blood and epithelia of animals, plants, hemolymph of insects, and venom of scorpions. The multitude of peptides discovered, more than 500, are cataloged and updated in a database (www.bbcm.univ.trieste.it/~tossi/antimic.html). The diverse occurrence and similar activities of antimicrobial peptides indicate an ancient origin and conserved role in host immunity to pathogens. 18,19 Indeed, during the last two decades, antimicrobial peptides have become well recognized as important within the innate and the humoral immune responses. 18.2.3 COMPOSITION AND STRUCTURE OF MICROBIAL CELL-PERMEATING PEPTIDES The naturally occurring antimicrobial peptides are normally 12–50 amino acids long (occasionally up to 80 amino acids) and share two main characteristics. First, they are polycationic with a positive net charge of more than +2 (due to an excess of primarily lysine and arginine residues). Second, they have the ability to form amphipathic structures with both positively charged and hydrophobic regions (see Figure 18.2b). The hydrophobic content is generally around 50% and this face promotes interaction with membrane lipids. The positively charged face promotes interaction with water and negatively charged lipids and cell wall structures. This organization is ideal for a molecule that needs to be soluble in water and also lipophylic. Apart from their positive charge and amphipathic features, antimicrobial peptides can be categorized into different structural classes (Figure 18.2a), including peptides composed of α-helices, β-sheet, loops, and extended sequences. The most common classes are linear peptides that form amphipathic α-helices in contact with membranes and the cystein-containing peptides, which are usually β-sheet peptides constrained by two to four disulfide bonds. Less common are linear peptides with a
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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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Page 350 and 351: Cell-Penetrating Peptide Conjugatio
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Page 370 and 371: Cell-Penetrating Peptides as Vector
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Page 402 and 403: 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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