Peptide helix mimics

In parallel to LXR agonists, apoA-I mimetic peptides also promote RCT. Specifically, they have been reported to facilitate cholesterol efflux from macrophages and decrease atherosclerosis in apoE null mice fed a Western diet [13, 16, 222-224], ApoA-I mimetics are small synthetic peptides that mimic the amphipathic a-helix of apoA-I and thus its functionality [225], Several apoA-I mimetic peptides are currently under preclinical trials and clinical development (namely, D-4F, L-4F, 5F, 6F, 7F, 5A, ATI-5261, and ETC642). The apoA-I mimetic peptides, D-4F and L-4F, showed great promise in early human trials [226] leading to a phase I/II study in humans with high-risk CVD [227],... 

Structural and functional studies of a synthetic peptide that mimics a proposed membrane inserting segment of a Bacillus thuringiensis delta-endotoxin have been conducted. An NMR study of a methanol solution of a synthetic 31-mer peptide corresponding to the sequence of a putative pore-forming segment of the CrylA(c) toxin showed that the peptide exists as an a-helix. Hie peptide forms discrete, characterizable channels in planar lipid bilayers. It is possible that this helix is a component of the transmembrane pore formed by Bacillus thuringiensis delta-endotoxins in vivo. 

Fig. 13 Stabilized helices and nonnatural helix mimetics several strategies that stabilize the a-helical conformation in peptides or mimic this domain with nonnatural scaffolds have been described. Recent advances include [1-peptide helices, terphenyl helix-mimetics, mini-proteins, peptoid helices, side-chain crosslinked a-helices, and the hydrogen bond surrogate (HBS) derived a-helices. Circles represent amino acid side-chain functionality (Reprinted from Henchey et al. [52], Copyright (2008) with permission from Elsevier)...

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... 

Robust peptide-derived approaches aim to identify a small drug-like molecule to mimic the peptide interactions. The primary peptide molecule is considered in these approaches as a tool compound to demonstrate that small molecules can compete with a given interaction. A variety of chemical, 3D structural and molecular modeling approaches are used to validate the essential 3D pharmacophore model which in turn is the basis for the design of the mimics. The chemical approaches include in addition to N- and C-terminal truncations a variety of positional scanning methods. Using alanine scans one can identify the key pharmacophore points D-amino-acid or proline scans allow stabilization of (i-turn structures cyclic scans bias the peptide or portions of the peptide in a particular conformation (a-helix, (i-turn and so on) other scans, like N-methyl-amino-acid scans and amide-bond-replacement (depsi-peptides) scans aim to improve the ADME properties." ... 

Helix induction can be augmented by mimicking natural mechanisms using a variety of synthetic expedients. In general, these approaches seek to either stabilize or mimic helix nucleation sites or to naturally or artificially secure side-chain linkages. In most cases, these transformations make use of additional synthetic procedures beyond standard peptide synthesis methodologies to juxtapose amino acids or essential elements thereof in a manner that mimics a protein helix. 

Nonpeptidic scaffolds may also be used to position carbonyl groups for the nucleation of helices. In the present case, three successive carbonyl groups are positioned in 3,6-dimethyl-4-oxo-2,3,4,5,6,7-hexahydro-l//-indole-3,6-dicarboxylic acid (11) (Scheme 5) to mimic those in the first turn of an a-helix.112" Peptide H-Glu-Ala-Leu-Ala-Lys-Ala-NH2 was attached to 11 through a linking residue and helix induction was examined by CD and NMR. 

To expand the utility of the hydrogen bond mimic, J (23) has been modified to allow for extension from the N-terminus of a hydrazone-linked cyclic peptide 148 This allows not only the use of the hydrogen bond mimic in preparing internal loops, but also the positioning of a helix nucleation site between two peptides to form supersecondary structures. To accomplish this, an a-amino group can be added to J to give J (26) (Scheme 14). Incorporation of linker J into a nucleation site using the procedure applied to 23 allows it to mimic an N-cap formed... 

Melittin, which is an amphipathic peptide from honeybee venom, consists of 26 amino acid residues and adopts different conformations from a random coil, to an a-helix, and to a self-assembled tetramer under certain aqueous environments see Fig. 9. We have carried out our systematic studies of the hydration dynamics in these three conformations using a single intrinsic tryptophan ( W19) as a molecular probe. The folded a-helix melittin was formed with lipid interactions to mimic physiological membrane-bound conditions. The self-assembled tetramer was prepared under high-salt concentration (NaCl = 2 M). The tryptophan emission of three structures under three different aqueous environments is 348.5 nm, 341 nm, and 333.5 nm, which represents different exposures of aqueous solution from complete in random-coil, to locating at the lipid surface of a nanochannel (50 A in diameter) in a-helix and to partially buried in tetramer. Figure 10 shows... 

The structure of the HA2 N-terminal fusion peptide has been probed by a combination of NMR and electron paramagnetic resonance (EPR) in detergent micelles that mimic the lipid bilayer, at both acid and neutral pHs (Han et al, 2001). At both acidic and neutral pH the structure is predominantly helical with a kink where it rises most prominently to the presumptive membrane surface. At lower pH the kink is stronger, there is additional 3io helix, and two charged residues are rotated out of the membrane plane. The stronger kink likely allows the peptide to become more deeply immersed, perhaps disrupting the membrane and facilitating fusion. 

Kaiser and colleagues (Fukushima et ai, 1980) showed that a 22-residue peptide can be synthesized entirely from Glu, Lys, and Leu arranged periodically in the typical class A distribution to form an am-phipathic a helix with equal polar and nonpolar faces. Indeed, as studied by quantitative ultrafiltration, gel-permeation chromatography, and circular dichroism, the peptide associated effectively with phospholipid and mimicked some of the physical and chemical properties of apoA-I (Fukushima a/., 1980 Kaiser and Kezdy, 1983, 1984 Nakagawa a/., 1985). Because of the presence of tandem repetitive amphipathic helical domains in apoA-I, a dimer of this 22-residue peptide was later synthesized and found to more closely mimic apoA-I than the monomer thus the study of peptide analogs supported the concept that 44-mers represent the minimal functional domain in apoA-I (Nakagawa et ai, 1985). 

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