12/14/14‐Helix Formation in 2:1 α/β‐Hybrid Peptides Containing Bicyclo[2.2.2]octane Ring Constraints

Abstract

The highly constrained β-amino acid ABOC induces different types of helices in β urea and 1:1 α/β amide oligomers. The latter can adopt 11/9- and 18/16-helical folds depending on the chain length in solution. Short peptides alternating proteinogenic α-amino acids and ABOC in a 2:1 α/β repeat pattern adopted an unprecedented and stable 12/14/14-helix. The structure was established through extensive NMR, molecular dynamics, and IR studies. While the 1:1 α-AA/ABOC helices diverged from the canonical α-helix, the helix formed by the 9-mer 2:1 α/β-peptide allowed the projection of the α-amino acid side chains in a spatial arrangement according to the α-helix. Such a finding constitutes an important step toward the conception of functional tools that use the ABOC residue as a potent helix inducer for biological applications.

12/10‐Helix in Mixed β‐Peptides Alternating Bicyclic and Acyclic β‐Amino Acids: Probing the Relationship between Bicyclic Side Chain and Helix Stability

“…Over the last few years, we investigated the ability of peptide sequences incorporating the ( S )‐1‐aminobicyclo[2.2.2]octane‐2‐carboxylic acid [( S )‐ABOC] residue, a constrained β 2, 3, 3 ‐trisubstituted bicyclic amino acid, to adopt well‐defined structures. We previously showed the high propensity of the ABOC residue to drive helical architectures in both oligoureas and hybrid‐oligoamides in alternation with α‐amino acids –. Importantly, the ABOC torsion angle values (typical average values φ =75°, θ =58°, ψ =−91°) were almost identical in these various edifices, highlighting the high rigidity of this moiety, which is of great interest to develop predictable and stable scaffolds.…”

1-Aminobicyclo[2.2.2]octane-2-carboxylic Acid and Derivatives As Chiral Constrained Bridged Scaffolds for Foldamers and Chiral Catalysts

“…39 On the other side, the 2:1 α-AA/(S)-ABOC sequences 23−25 adopted a single original 12/14/14-helix in solution stabilized by hydrogen bonds with opposite directionality, forming intramolecular 12-and 14-membered pseudocycles (Figure 1C). 3 The geometry of hexamer 24 was particularly attractive since the orientation of α-AA side chains matched rather well with those in the canonical α-helix. Finally, attempts to further dilute the ABOC residue among α-amino acids failed to give rise to stable architectures; e.g., short 1:3 α-AA/(S)-ABOC oligomers did not fold (unpublished results).…”

Selectivity Modulation and Structure of α/aza‐β3 Cyclic Antimicrobial Peptides

“…[15][16][17] Peptidomimetic compounds can recapitulate the structure and functiono fn atural AMPs while circumventing their susceptibility to protease degradation. [18] Beta-and g-peptides, [19][20][21][22][23][24][25][26][27][28][29][30][31][32] peptoids, [33][34][35][36] b-peptoids, [37,38] and oligoureas [39] have generated significant interesta sp otentialt herapeutic agents, especially since they can adopts table and predictables econdary structures and are anticipated to disturbt he bacterial cell membrane similarly to AMPs.O ur investigationsf ocus on the incorporationo fa za-b 3 -amino acids in natural peptides equences to modulate their bioavailability and activity.L inear and cyclic aza-b 3 -peptides can adopt well-definedc onformations stabilized by ah ydrogen-bond network leading to bifidic eightmembered pseudocycles forming hydrazino turns (N-N turns) in the solid state and in organic media. [40,41] Although the azab 3 -amino acid Ns tereocenter bearing the side chains is not fixed and can adopt the l or d configuration, the cyclic constraints ignificantly reduces the inversion rate at the Nc enter.…”

“…Peptidomimetic compounds can recapitulate the structure and function of natural AMPs while circumventing their susceptibility to protease degradation . Beta‐ and γ‐peptides, peptoids, β‐peptoids, and oligoureas have generated significant interest as potential therapeutic agents, especially since they can adopt stable and predictable secondary structures and are anticipated to disturb the bacterial cell membrane similarly to AMPs. Our investigations focus on the incorporation of aza‐β 3 ‐amino acids in natural peptide sequences to modulate their bioavailability and activity.…”