The Smallest α,γ-Peptide Nanotubulet Segments:  Cyclic α,γ-Tetrapeptide Dimers

Abstract

[structure: see text] Cyclic tetrapeptides in which alpha-amino acids alternate with cis-3-aminocycloalkanecarboxylic acids dimerize by forming hydrogen bonds between their alpha-faces but not between their gamma-faces, establishing the minimal structural requirements for the novel alpha,gamma-peptide hybrids SPN.

Solid state and solution conformations of a hybrid αγααγα hexapeptide. Characterization of a backbone expanded analog of the α‐polypeptide 310‐helix

“…Multiply substituted γ amino acid residues, pose significant synthetic and stereochemical problems because of the presence of multiple chiral centers 4, 24, 25. Therefore, the conformational analysis of hybrid sequences containing γ residues have been limited 26–28. We have recently described the structural properties of short peptides containing the conformationally constrained achiral β,β‐disubstituted γ residue, gabapentin (1‐(aminomethyl)cyclohexaneacetic acid, Gpn) 29.…”

Self‐Assembling Cyclic Peptide‐Based Nanomaterials

“…Cyclic octapeptides presented similar properties as hexapeptide homologs, showing association constant values of 340 M −1 for the γ −γ interaction and high-affinity association (Ka larger than 10 5 M −1 ) for the α−α interaction [42]. On the other hand, cyclic tetrapeptides do not self-assemble through their γ -face, and present small association constant values (Ka = 15 M −1 ) for α−α interaction, suggesting that the rigidity of the 24-membered ring precludes the cyclic unit from adopting the flat conformation required for the self-assembly, which was confirmed by analysis of the corresponding X-ray structure [43,44].…”

“…With a view to favoring adoption of the required all-trans flat conformation, our group have recently been working on the design, synthesis, characterization, and application of a new class of cyclic peptides in which α-amino acid residues alternate with cis-3 aminocycloalkanecarboxylic acids (γ -Acas) [41][42][43][44][45][46][47][48][49]. The cycloalkane rings of these peptide units not only direct a hydrophobic, functionalizable methylene toward the interior of the cyclic peptide ring (thus allowing manipulation of the behavior of the inner cavity of the corresponding nanotubular structure) but also ensure the flatness and rigidity of the cycloalkane segments of the peptide backbone.…”

“…Seeking to control the internal diameter of the corresponding nanotubular structures, we have performed the synthesis of tetra- [43,44], hexa- [45], octa- [47], deca- [47], and dodecapeptides [47] made of alternating α-amino acid and N-methyl γ -Acp residues with backbones containing between 16 and 48 atoms and diameter ranging from 4 to 17Å. All the cyclic units form the expected dimers through their α-face with high-affinity association (Ka > 10 5 M −1 ) in nonpolar solvents, except for the four-residue γ -Acp-based cyclic peptide in which the association constant was estimated to be 47 M −1 [43,44]. The ability of this kind of peptide rings to form stable nanocylindrical homodimers was confirmed by NMR, FT-IR spectroscopy, and X-ray diffraction data (Figure 1.13).…”

Perspectives on main‐chain hydrogen bonded supramolecular polymers

“…Collectively, the linear arrays of two or three donor–acceptor groups have association constants that are still too small (<10 6 L mol −1 ) to give high DP, unless other stabilizing factors are present, for example a liquid crystalline environment that favors intermolecular interactions 62–64. Macrocyclic peptides with alternating D ‐ and L ‐amino acids, such as those reported by Ghadiri and co‐workers,65–67 Seebach et al ,68 and others,69–71 pre‐organize amide groups above and below the macrocycle for facile columnar self‐assembly. The assembled nanotubes were stable to a wide range of pH and solvents.…”