Homogeneous and Robust Polyproline Type I Helices from Peptoids with Nonaromatic α-Chiral Side Chains

Abstract

Peptoids that are oligomers of N-substituted glycines represent a class of peptide mimics with great potential in areas ranging from medicinal chemistry to biomaterial science. Controlling the equilibria between the cis and trans conformations of their backbone amides is the major hurdle to overcome for the construction of discrete folded structures, particularly for the development of all-cis polyproline type I (PPI) helices, as tools for modulating biological functions. The prominent role of backbone to side chain electronic interactions (n → π*) and side chains bulkiness in promoting cis-amides was essentially investigated with peptoid aromatic side chains, among which the chiral 1-naphthylethyl (1npe) group yielded the best results. We have explored for the first time the possibility to achieve similar performances with a sterically hindered α-chiral aliphatic side chain. Herein, we report on the synthesis and detailed conformational analysis of a series of (S)-N-(1-tert-butylethyl)glycine (Ns1tbe) peptoid homo-oligomers. The X-ray crystal structure of an Ns1tbe pentamer revealed an all-cis PPI helix, and the CD curves of the Ns1tbe oligomers also resemble those of PPI peptide helices. Interestingly, the CD data reported here are the first for any conformationally homogeneous helical peptoids containing only α-chiral aliphatic side chains. Finally we also synthesized and analyzed two mixed oligomers composed of NtBu and Ns1tbe monomers. Strikingly, the solid state structure of the mixed oligomer Ac-(tBu)-(s1tbe)-(tBu)-COOtBu, the longest to be solved for any linear peptoid, revealed a PPI helix of great regularity despite the presence of only 50% of chiral side chain in the sequence.

Sequence and Structure of Peptoid Oligomers Can Tune the Photoluminescence of an Embedded Ruthenium Dye

“…The average chain length of 2.2–2.4 nm is in agreement with the length of an N r1tbe containing peptoid homopentamer, the crystal structure of which was recently published . Specific arrangements of helical bundles can be also observed (marked in red circles in Figure a) with an average space width between peptoids of 2.5 Å (marked by two white pointing arrows in the inset of Figure b), which can be assigned to hydrophobic interactions and/or π–π stacking between helices from the same bundle.…”

“…The CD spectra of 5SP and 5RP having N spe or N rpe monomers, respectively, show the expected characteristic double minima or maxima with bands at 203 and 220 nm. The CD spectrum of 5SC shows characteristic two minima at 196 and 222 nm and a maximum at 208 nm, and the spectra of 5RTB exhibits two maxima at 198 and 223 nm and one minimum at 211 nm as was expected for oligomers that contain N sch and N r1tbe groups, correspondingly . The CD spectrum of 5SM exhibits a minimum near 190 nm, characteristic of a chiral yet unstructured peptoid and 5PM , being achiral, does not exhibit a CD spectrum (see the Supporting Information).…”

“…The CD spectra of peptoids having only phenylethyl side chains (phenylethyl peptoids) exhibit a characteristic double minima ( N spe) or a double maxima ( N rpe) with bands near 200 nm and 220 nm, that are associated with trans ‐amide bond and cis ‐amide bond conformations, respectively . Peptoids containing only tertiary butyl groups or cyclohexyl groups, on the other hand, were shown to adopt all‐ cis PP‐I helices and their CD spectra resemble these of PP‐I peptide helices, with two minima near 190 and 225 nm and a maximum near 210 nm . The CD spectra of 5SP and 5RP having N spe or N rpe monomers, respectively, show the expected characteristic double minima or maxima with bands at 203 and 220 nm.…”

Stabilising Peptoid Helices Using Non‐Chiral Fluoroalkyl Monomers

“…However, given their tertiary amide backbone, peptoids lack the capacity to form hydrogen bonds so that their secondary structures are dominated by relatively weak interactions. Considerable efforts have been devoted to try and understand the relationships between a peptoid primary sequence and its folded structure 6, 7, 8, 9, 10. The cis / trans isomerization of the tertiary amide bond is the major cause of conformational heterogeneity in peptoid oligomers.…”

“…Gorske and Blackwell found that the synergistic application of steric and non‐covalent n→π* interactions (NCIs) in aromatic systems could also be used to design stable cis ‐amide peptoid monomers (e.g., Ns 1npe, 2 ) 8. However, it is not possible to use the aforementioned NCIs to stabilize the cis ‐amide conformation of alkyl peptoid monomers, and thus the design of stable peptoid helices remains dominated by the use of chiral aromatic residues (e.g., 1 and 2 ) 9. Recently, Faure, Taillefumier, and co‐workers exploited steric effects in the design of a non‐chiral t Bu alkyl monomer that has a clear cis ‐amide preference ( Nt Bu, 3 ) 10.…”