Foldamers Containing Multiple Diketopiperazines “Foldamers

oligomers that adopt a well-defined secondary structure stabilized by non-covalent interactions, were developed to mimic the conformations and abilities of proteins and nucleic acids. Foldamers are often assembled chemically by coupling unnatural monomers into sequence-specific oligomers. Various applications have been reported using different foldamers: p-peptides [83, 84], peptoids [85, 86], aryl-based oligomers [87-89], and others [90-93]. Several foldamers containing DKPs have been reported to mimic protein secondary structure.

в-Bend Ribbon Mimics

P-bend ribbon is normally considered a subtype of the peptide 3i0 helix featuring a succession of repeating p-turn conformations, in which the carbonyl group of residue i is hydrogen bonded to the NH of the i + 3 residue [94]. Peptides containing repeating units composed of proline or a-aminoisobutyric acid (Aib) often adopt this secondary structure [95, 96]. In 2010, Piarulli and co-workers reported p-bend

Fig. 19 (a) p-Bend ribbon 104 composed of amino acid DKPs 103; (b) SD simulation of tetramer 104

ribbon 104 formed by linking four-amino acid DKP monomers 103 through amide bonds (Fig. 19a) [97].

Tetramer 104 exhibited characteristics of a p-bend ribbon in NMR and CD spectroscopic experiments and stochastic dynamic (SD) simulations. For example, titration of 104 with deuterated methanol in d6-DMSO revealed intramolecular hydrogen bonds between exocyclic amide protons, which exchanged at slower rates compared to the DKP N-H protons. Moreover, the exocyclic amide and methylene protons exhibited NOE correlations (red arrows in Fig. 19a). The CD spectrum of tetramer 104 displayed a typical Cotton effect with strong and weak negative maximum, respectively, at 200 and 215 nm, similar to oligopeptides that are known to adopt ten-member hydrogen-bonded conformations. The spectroscopic evidence and SD simulations, all indicated that the DKP scaffolds pre-organized tetramer 104 to adopt a conformer featuring repeating ten-member hydrogen bonds (Fig. 19b).

 
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