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Microbial Membrane-Permeating Peptides and Their Applications 389 resistance and resistance to antimicrobial peptides does not appear to arise rapidly. 57,58 This is probably because the antimicrobial peptide-killing mechanisms are largely distinct from those of small molecule antibiotics and antimicrobial peptides are typically cidal rather than static above their threshold concentration for activity. Another advantage with antimicrobial peptides is that their cell-permeating activities can potentiate conventional antibiotics when used in combination. 57 As with all new drug ideas, several levels of difficulty exist with antimicrobial peptide development and the problems apply to most potential applications of cellpermeating peptides. Natural antimicrobial peptides are produced at site or delivered to the place of infection by white blood cells that produce the peptides, whereas peptides used as drugs must find their own way. Cell-permeating peptides are larger than most drugs and typically show poor stability and distribution properties in the body. Other problems are the uncertain design and development rules for antimicrobial peptides, in vitro studies provide only poor indications of in vivo efficacy, and peptides can be expensive to produce and purify. Because of these problems, screening efforts that show initial success can prove ultimately disappointing. Given the uncertain mixture of positive and negative properties of antimicrobial peptides, the area is still regarded as rather risky and large pharmaceutical companies have shown relatively little interest (Table 18.2). Nevertheless, evidence from animal studies and clinical trials shows that antimicrobial peptides can provide effective antimicrobials. 59-63 Also, many problems that limit efficacy in vivo and efficient large scale production have been solved. 1 Finally, it has been very difficult to develop effective new small molecular weight antimicrobials that do not succumb to resistance. 64,65 Therefore, whereas the unconventional nature of antimicrobial peptides creates difficulties for clinical development, it is important to recognize that the unique properties of these peptides also provide very valuable alternative strategies. For the future, it seems likely that we will soon see drug approval for antimicrobial peptides for topical or oral therapy. 18.5.2 MICROBIAL CELL-PERMEATING PEPTIDES AS CARRIERS FOR FOREIGN SUBSTANCE DELIVERY Microbial cells are typically very resistant to foreign substance uptake. As discussed above, this resistance is provided by the outer cell wall, which acts as a sieve blocking entry of many harmful compounds found in microbial environments. 12,66 Only small molecular weight substances are able to efficiently enter microorganisms by diffusion alone. Unfortunately, these barriers also limit the cell uptake of antimicrobial agents that otherwise would be useful in medicine. Most antibiotics and antimicrobials used in the clinic are small molecular weight substances, less than 500 g per mol. The observation that antimicrobial peptides can permeate cell barriers is surprising and opens possibilities to use these peptides to expand the range of substances that could be used as drugs against microorganisms. The idea of using peptides to deliver foreign substances into microorganisms was introduced almost 30 years ago. The initial idea was to use two or three residue peptides that are substrates for oligopeptide permeases and link impermeant toxic compounds to the peptides for delivery (Figure 18.5). Im<strong>press</strong>ive results were
TABLE 18.2 Antimicrobial Peptides or Derivatives in Clinical Development Clinical application Peptide Type Administration Company Stage of development Diabetic foot ulcers MSI-78 (magainin analog) α-helical Topical Genaera (magainin) Clinical trials completed Catheter infection MBI-226 α -helical Topical Micrologix Biothech Clinical Muscositis IB-367 (protegrin analog) β-sheet Oral Intrabiotics Clinical Gingivitis P-113 (histatin analog) unordered Oral Periodontix Clinical Antifungal Systemic Entomed Preclinical Meningococcal meningitis Neuprex (BPI-fragment) α-helical Systemic Xoma Clinical 390 Cell-Penetrating Peptides: Processes and Applications
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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 360 and 361: 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
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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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