Helical screw‐sense preferences of peptides based on chiral, C^α‐tetrasubstituted α‐amino acids

Abstract

The preferred helical screw senses of chiral α-amino acids with a C(α)-tetrasubstituted α-carbon atom, as determined in the crystal state by X-ray diffraction analyses on derivatives and peptides, are reviewed. This survey covers C(α)-methylated and C(α)-ethylated α-amino acids, as well as α-amino acids cyclized on the α-carbon, including those characterized by the combination of lack of chirality at the α-carbon with either side-chain or axial chirality. Although, in general, chiral C(α)-tetrasubstituted α-amino acids show a less pronounced bias toward a single helical screw sense than their proteinogenic (C(α)-trisubstituted) counterparts, our analysis highlights significant differences in terms of magnitude and direction of such a bias among the various sub-families of residues, and between individual amino acids within each sub-family as well. The experimental findings can be rationalized, at least in part, on the basis of steric considerations.

Helical l–Leu‐Based Peptides Having Chiral Five‐Membered Carbocyclic Ring Amino Acids with an Ethylene Acetal Moiety

“…[1][2][3][4][5][6] As a dAA, α-aminoisobutyric acid (Aib) has widely been used to induce helical structures. A right-handed (P) 3 10 -helix is induced in relatively shorter L-amino acid-based peptides having a high Aib content; however, a right-handed (P) α-helix is preferentially formed in relatively longer L-amino acid-based peptides having a low Aib content.…”

“…[16][17][18][19] We previously reported the synthesis of a chiral five-membered carbocyclic ring dAA: (R)-or (S)-amino-3,3-(ethylenedioxy)cyclopentanecarboxylic acid (Ac 5 c 3EG ) with an ethylene acetal moiety, in which the α-carbon atom was a chiral center, and the helical structures of its homo-chiral homopeptides. [20] In the present study, to reveal the influence of (S)-or (R)-Ac 5 [a]…”

Structural Development of Cell-Penetrating Peptides Containing Cationic Proline Derivatives

“…The introduction of unnatural amino acids, such as α,α-disubstituted amino acids (dAAs) or cyclized β-amino acids have been shown to enhance peptide helical structures. [5][6][7] To investigate the effects of the secondary structure of CPPs on their cell membrane permeability, we designed and synthesized novel CPP derivatives containing dAAs residues such as α-amino-isobutyric acid (Aib). 8) For example, the nonapeptides FAM-βAla-(L-Arg-L-Arg-Aib) 3 -NH 2 (1, FAM: 6-fluorescein), FAM-βAla-(L-Arg-D-Arg-Aib) 3 -NH 2 (2) and FAM-βAla-(D-Arg-D-Arg-Aib) 3 -NH 2 (ent-1) were synthesized, and their cell-penetrating ability were evaluated.…”

Refoldable Foldamers: Global Conformational Switching by Deletion or Insertion of a Single Hydrogen Bond

“…The two screw‐sense conformers of an Aib oligomer may be desymmetrised by ligation to a chiral terminus,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 which leads to an imbalance in the population of the two interconverting screw‐sense conformers 34,35. This imbalance may be quantified by NMR,27 and a C terminal AlaNHR residue, for example, may induce a 99:1 preference for right‐handed screw sense in an attached Aib oligomer chain 25.…”