Amphipathic peptide

AMPHIPATHIC a -HEUCAL PEPTIDES AMPHIPATHIC, CYCUC P-SHEET PEPTIDES... 

For rational de novo design of a-helical and cyclic /i-sheet antimicrobial peptides, it is known that optimization of the efficacy of such antibiotics depends on a balance of peptide features (1) for amphipathic a-helical peptides, antimicrobial potency depends upon peptide amphipathicity [224,225], hydro-... 

FIGURE 10.35 The amino acid sequences of several amphipathic peptide antibiotics, a-Helices formed from these peptides cluster polar residues on one face of the helix, with nonpolar residues at other positions. 

The magaiitins are a class of hnear, cationic, faciaUy amphipathic and hehcal antibacterial peptides derived from frog skin [51]. The magaiitins exhibit highly selective and potent antimicrobial activity against a broad spectrum of organisms [52, 53]. As these peptides are faciaUy amphipathic, the magainins have a cationic heli-... 

As such, the magainins provide a useful initial target for peptoid-based peptido-mimetic efforts. Since the helical structure and sequence patterning of these peptides seem primarily responsible for their antibacterial activity and specificity, it is conceivable that an appropriately designed, non-peptide helix should be capable of these same activities. As previously described (Section 1.6.2), peptoids have been shown to form remarkably stable hehces, with physical characterishcs similar to those of peptide polyprohne type-I hehces (e.g. cis-amide bonds, three residues per helical turn, and 6A pitch). A faciaUy amphipathic peptoid helix design, based on the magainin structural motif, would therefore incorporate cationic residues, hydrophobic aromatic residues, and hydrophobic aliphathic residues with threefold sequence periodicity. 

Bruni, R., Taeusch, H.W., and Waring, A.J. Surfactant protein B Lipid interactions of synthetic peptides representing the amino-terminal amphipathic domain. Proc. Natl. Acad. Sci. USA 1991, 88, 7451-7455. 

Next, the CD spectra of the backbone 2 aPNA Ac-Cys -Lys-Ser -Ala-Ala-Lys-Ser -Ala-Ala-Lys-SerhAla-Ala-Lys-Ser -Ala-Ala-Lys-Ser -Gly-Lys-NH2, was measured as a function of pH in phosphate buffer. At pH 7, the secondary structure of this aPNA was largely random coil. However, the a-hehcity of this aPNA increased with the pH until it reached a maximum at pH 11. Analogous pH-depen-dent secondary structure has also been reported for the amphipathic KALA peptide Trp-Glu-Ala-Lys-Leu-Ala-[Lys-Ala-Leu-Ala]2-Lys-His-Leu-Ala-Lys-Ala-Leu-Ala-Lys-Ala-Leue-Lys-Ala-Cys-Glu-Ala-OH [53]. In our case however, maximum a-helicity... 

These studies showed thaL in the absence of nucleic acid, the backbone 1 aPNA had significant a-hehcal content at pH 7 whereas the backbone 2 aPNA was largely in a random coil conformation at physiological pH. The latter aPNA did become a-helical at higher pHs in a manner reminiscent of the structurally related amphipathic peptides. 

Oehlke and coworkers have described the cellular uptake properties of a simple a-hehcal amphipathic model peptide sequence (Lys-Leu-Ala-Leu-Lys-Leu-Ala-Leu-Lys-Ala-Leu-Lys-Ala-Ala-Leu-Lys-Leu-Ala) in the context of a drug delivery vehicle [72]. On the basis of the data presented, it was proposed that non-endocytosis mechanism(s) were involved in the uptake into mammalian cells. The similarity between our b2 aPNA-sequence to that of this amphipathic model peptide makes it tempting to suggest that a similar uptake mechanism is involved in the cellular uptake of aPNAs. Further experimentation is necessary to test this hypothesis. 

Amphipathic peptides contain amino acid sequences that allow them to adopt membrane active conformations [219]. Usually amphipathic peptides contain a sequence with both hydrophobic amino acids (e.g., isoleucine, valine) and hydrophilic amino acids (e.g., glutamic acid, aspartic acid). These sequences allow the peptide to interact with lipid bilayer. Depending on the peptide sequence these peptides may form a-helix or j6-sheet conformation [219]. They may also interact with different parts of the bilayer. Importantly, these interactions result in a leaky lipid bilayer and, therefore, these features are quite interesting for drug delivery application. Obviously, many of these peptides are toxic due to their strong membrane interactions. 

Amphipathic peptides are important for the viruses when they enter the interior. Many viruses have amphipathic peptides on their surface. A classic example is Haemophilus influenzae [208]. Amphipathic peptide on the viral surface undergoes a conformational change when the endosomal pH is acidified and, subsequently, this peptide is able to fuse with the endosomal bilayer. Consequently, the virus is able to escape from the endosome to the cytoplasm. Many amphipathic peptides are pH-dependent so that they are activated in the endosomal compartment [219]. 

Zhou, N. E., Mant, C. T., and Hodges, R. S., Effect of preferred binding domains on peptide retention in reversed-phase chromatography amphipathic... 

Rege, K., Patel, S.J., Megeed, Z., and Yarmush, M.L. (2007) Amphipathic peptide-based fusion peptides and immunoconjugates for the targeted ablation of prostate cancer cells. Cancer Res. 67, 6368-6375. 

Blazyk J, Wiegand R, Klein J, Hammer J, Epand RM, Epand RF, Maloy WL, Kari UP (2001) A novel linear amphipathic beta-sheet cationic antimicrobial peptide with enhanced selectivity for bacterial lipids. J Biol Chem 276 27899-27906... 

A frequently used strategy to couple peptides to the surface of liposomes consists in the use hydrophobic/amphipathic anchors that are functionalized with maleimide or bromoacetyl groups, i.e., thiol-reactive functions, which give by reaction with HS-peptides very stable thioether linkages. These functions are conveniently introduced into hydrophobic anchors such as phospholipids, e.g., PE (9,10), the adjuvant PamsCAG (11) or cholesterol... 

Both thiol-derivatized peptides were conjugated to the surface of small unilamellar vesicles (PC/PG/Chol 75/20/50 65nm dia.) containing a thiol-reactive functionalized PamsCSS anchor (11,59), i.e., an amphipathic triacylated lipopeptide chosen for its adjuvanticity, its activation of DCs... 

A common characteristic of CPPs is that they contain a minimal motif of less than 20 amino acids rich in basic residues. There are two subclasses of CPPs the first class consists of amphipathic helical peptides, where lysine is the predominant supplier of the positive charge, for example model amphipathic peptide (MAP) and transportan, whereas the second group, which includes TAT and penetratin, is rich in arginine residues (48-60,86). 

Fusogenic peptides, derived from viral sources, are particularly well characterized (107 111). The amphipathic peptide from the A-terminal region of the hemagglutinin (HA)-2 subunit of HA was one of the first such peptides described, and, subsequently, a range of influenza-derived peptides... 

A synthetic peptide has been designed to mimic the effects of viral fusogenic properties (114,115). It consists of 30 amino acids with the major repeat of Glu-Ala-Leu-Ala so, it is referred to as a GALA peptide. It undergoes a conversion from an aperiodic conformation at neutral pH and becomes an amphipathic alpha helix at pH 5. In the more acidic environment, the peptide interacts with lipid bilayers (114,115). GALA has been incorporated into transferrin-targeted liposome, with the effect of significantly... 

Parente RA, Nir S, Szoka FC Jr. pH-dependent fusion of phosphatidylcholine small vesicles. Induction by a synthetic amphipathic peptide. J Biol Chem 1988 263 4724 730. 

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