ω-Amino Acids in Peptide Design. Crystal Structures and Solution Conformations of Peptide Helices Containing a β-Alanyl-γ-Aminobutyryl Segment

Insertion of achiral ω-amino acids into peptide sequences results in replacement of scissile peptide bonds by proteolytically stable C−C bonds. This provides a convenient means of creating peptidomimetics. The present study establishes the preservation of helical structures in octa- and undecapeptides with centrally located β- and γ-amino acids in the sequence. X-ray diffraction analyses of single crystals and NMR studies have been used to investigate the extent of perturbations of a regular 310- or α-helix by the introduction of (−CH2−)n groups into the backbone by the use of the β-Ala-γ-Abu segment (β-Ala = β-alanine, γ-Abu = γ-aminobutyric acid), which is formally homomorphous with a (Gly)3 segment. In crystals, the octapeptide Boc-Leu-Aib-Val-β-Ala-γ-Abu-Leu-Aib-Val-OMe (1) and the undecapeptide Boc-Leu-Aib-Val-β-Ala-γ-Abu-Leu-Aib-Val-Ala-Leu-Aib-OMe (2) retain their helical motifs with minor bulges. Five new types of 4 → 1, 5 → 1, and 6 → 1 hydrogen bond rings are formed with up to three extra CH2 mo...