Amino acids self-assembling cyclic peptides

Peptides composed of various coded and noncoded amino acid residues self-assemble to form various types of supramolecular architectures, including supramolecular helices and sheets, nanotubes, nanorods, nanovesicles, and nanofibers. The higher-order self-assembly of supramolecular (3-sheets or supramolecular helices composed of short synthetic acyclic peptides leads to the formation of amyloid-like fibrils. Synthetic cyclic peptides were used in supramolecular chemistry as molecular scaffolding for artificial receptors, so as to host various chiral and achiral ions and other small neutral substrates. Cyclic peptides also self-assemble like their acyclic counterparts to form supramolecular structures, including hollow nanotubes. Self-assembling cyclic peptides can be served as artificial ion channels, and some of them exhibit potential antimicrobial activities against drug-resistant bacteria. 

The self-assembling cyclic D,L-cc-peptide nanotubes described demonstrate high stability on surfaces even after two months exposure to ambient temperature. NDI peptide nanotubes 18 may provide a facile method for the preparation of a new class of synthetic biomaterials [16b, 34a]. Recently Sanders and co-workers demonstrated the formation of amino acid-derived NDI hydrogen-bonded supramo-lecular organic M-helical nanotubes in nonpolar solvents and also in the solid state [34b]. The hydrogen-bonded supramolecular nature of the helical nanotubes was confirmed by the circular dichroism (CD) spectrum in chloroform with the addition of methanol, destruction of the supramolecular nanotubes was observed, due to the capabilities of such an aprotic solvent to compete for hydrogen-bond interactions [34b]. 

A different kind of self-assembled nanotubes (Figure 4.12) are spontaneously built from cyclic peptides made up of alternating D- andL-amino acids. As predicted by DeSantis group in the mid 1970s [43], the octapeptide cyc/o-[-(D-Ala-Glu-Z)-Ala-Gln)2] 94 [44a] is approximately planar with NH and C=0 bonds orientated perpendicularly to the mean plane of the macro-ring thus... 

Fig. 3. (a) Chemical structure of a synthetic cyclic peptide composed of an alternating sequence of D- and L-amino acids. The side chains of the amino acids have been chosen such that the peripheral functional groups of the flat rings are hydrophobic and allow insertion into lipid bilayers, (b) Proposed structure of a self-assembled transmembrane pore comprised of hydrogen bonded cyclic peptides. The channel is stabilized by hydrogen bonds between the peptide backbones of the individual molecules. These synthetic pores have been demonstrated to form ion channels in lipid bilayers (71). 

Two molecules of the ion-channel-forming peptide gramicidin, which contains alternating L- and D-amino acids, have been shown to form a membrane-spanning P-helix. The alternation of L- and D-amino acids is a feature of a series of cyclic peptides that self-assemble into membrane spanning nanotubes. P-Helices have now also been shown to occur as a structural element in proteins consisting only of L-a-amino acids, viz. in the enzyme pectate lyase. Related to the naturally... 

The cyclic peptide approach to nanotubes has some advautages over all other methods. In addition to diameter control, one can highlight that the properties of the outer surface of the nanotube can easily be modified by varying the amino acid side chains. In addition, due to the Cn symmetry of the backbone skeleton, nonsymmet-rical CPs can form an infinite number of different SPN (Figure 23b). This phenomenon is based on the interstrand rotation between two consecutive CPs, to form nonequivalent interactions for each j8-sheet. Appropriate unit design and optimization of conditions for self-assembly allows the nanotube properties to be tailored for specific applications. As a result, SPN can be used as (or in) porous solid materials, soluble cylindrical supermolecules, ion channels and other transmembrane pores, soUd-supported ion sensors, antimicrobial and cytotoxic agents, and nanocluster composites. A recent review published by Granja et al. includes the most relevant examples in this area. ... 

In 1994, Ghadiri s group created the first transmembrane nanotube to self-assemble in a lipid bilayer, by selecting hydrophobic side chains on the cyclic d,l-o -CPs such as cyclo-[L-Gln-(D-Leu-L-Trp)3-D-Leu-] (Figure 24). Since then, several similar structures have also been stud-ied and it was observed in all cases that when the amino acid sequence is dominated by hydrophobic amino acids, the resulting nanotube is oriented nearly parallel to the lipid alkyl chains, as required for a transmembrane channel, while peptide nanotubes formed from amphi-pathic cyclic peptides lie parallel to the membrane plane. Increasing the size of the cyclic peptide, for example, by using cyclo-[L-Gln-(D-Leu-L-Trp)4-o-Leu-], as expected. 

One of the most well-developed system that exemplifies the stacked-disk motif is the work of Ghadiri and coworkers on cyclic D,L-peptides [89,91-93]. The disks are held together through hydrogen bonds and intermolecular contacts between the peptide side chains. The potential for derivatization and functionalization is great because the disks are made from amino acids. These materials have shown the ability to assemble into lipid bilayers and transport ions across them. In addition these materials have recently been shown to act as self-assembled antibacterial agents with utility as therapeutics [93]. There are other systems that have been synthesized from shape persistent macrocycles to assemble into tubes [91,94]. 

Fig. 8.9 Nanotubes fonned from hydrogen bonding-induced self-assembly of cyclic -peptides, a Stracture of cyclic peptide containing -amino acids with diifcm nt chirality, b The corresponding stacking model of the three isomers in the solid stale (Me substituents and H atoms on the backbones are omitted for clarity). Re ninted with permission from Ref [44]. Copyright 1997, Wiley-VCH Verlag Gmbh and Co. KGaA, Weinheim...

Dory and co-workers synthesized a tripeptide composed of a, -unsaturated (5-amino acids (Fig. 8.10a) [45]. The trans geometry of the vinyl group was used to induce the peptide to adopt a flat conformation required for the self-assembling process. In a similar way to the nanombes from y5-peptides, the peptide backbone has an even number of atoms between the carbonyl and amino groups of each residue. As a result, all the hydrogen bonds were parallel in the nanotube (Fig. 8.10b). The same group further extended this pattern to di-, tri-, and tetrapeptides of -amino acids with a trans yS,(5-double bond (Fig. 8.10c). AU of these cyclic peptides were found to self-assemble into hydrogen bonded nanotubes [46]. 

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