N,N‘-Linked Oligoureas as Foldamers: Chain Length Requirements for Helix Formation in Protic Solvent Investigated by Circular Dichroism, NMR Spectroscopy, and Molecular Dynamics

Abstract

N,N'-linked oligoureas with proteinogenic side chains are peptide backbone mimetics belonging to the gamma-peptide lineage. In pyridine, heptamer 4 adopts a stable helical fold reminiscent of the 2.6(14) helical structure proposed for gamma-peptide foldamers. In the present study, we have used a combination of CD and NMR spectroscopies to correlate far-UV chiroptical properties and conformational preferences of oligoureas as a function of chain length from tetramer to nonamer. Both the intensity of the CD spectra and NMR chemical shift differences between alphaCH2 diastereotopic protons experienced a marked increase for oligomers between four and seven residues. No major change in CD spectra occurred between seven and nine residues, thus suggesting that seven residues could be the minimum length required for stabilizing a dominant conformation. Unexpectedly, in-depth NMR conformational investigation of heptamer 4 in CD3OH revealed that the 2.5 helix probably coexists with partially (un)folded conformations and that Z-E urea isomerization occurs, to some degree, along the backbone. Removing unfavorable electrostatic interactions at the amino terminal end of 4 and adding one H-bond acceptor by acylation with alkyl isocyanate (4 --> 7) was found to reinforce the 2.5 helical population. The stability of the 2.5 helical fold in MeOH is further discussed in light of unrestrained molecular dynamics (MD) simulation. Taken together, these new data provide additional insight into the folding propensity of oligoureas in protic solvent and should be of practical value for the design of helical bioactive oligoureas.

The Urea Renaissance

“…[27] N,N'-Linked oligoureas with proteinogenic side chains (13, Figure 3) are mimics of peptides whose preferred helical conformation results from intramolecular hydrogen bonds. [28,29] Those foldamers are unique scaffolds for potential use in a range of biological and biomedical applications. [30] Glycoluril and formaldehyde condense under acidic conditions to deliver the cucurbit[n]urils 14 (Figure 4), which consist of n glycoluril units that are joined to the next one by two methylene bridges to form a closed band in which the urea oxygen atoms are tilted inwards, thus forming a partly enclosed cavity.…”

Die Harnstoff‐Renaissance

“…[27] N,N'-Gekuppelte Oligoharnstoffe mit proteinogenen Seitenketten (13; Abbildung 3) wirken als Mimetika von Peptiden, deren bevorzugte schraubenfçrmige Konformation aus intramolekularen Wasserstoffbrücken resultiert. [28,29] Solche Foldamere sind einzigartige Gerüste für eine Reihe von biologischen und biomedizinischen Anwendungen. [30] Glycoluril und Formaldehyd kondensieren unter sauren Bedingungen zu den Cucurbit[n]urilen (14; Abbildung 4), die (14) und Cucurbit [7]uril (14a).…”

Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides

“…Poly-N-substituted glycines (peptoids) comprise another class of peptidomimetics that differ from peptides only in that peptoid side chains are attached to the backbone amide nitrogen rather than to the ␣-carbon (27), making them protease-resistant (28). More than any of the other peptidomimetic systems under study (29), including ␤-peptides (26,30), ␤-peptoids (31), oligoureas (32), and oligo(phenylene ethynylene)s (33), peptoids (34)(35)(36) are particularly well suited for AMP mimicry because they are easily synthesized on solid phase (by using conventional peptide synthesis equipment) with access to diverse sequences at relatively low cost (27). Any chemical functionality available as a primary amine can be incorporated via a submonomer synthetic method (27); thus, peptoids are highly and finely tunable.…”