Omega amino acids in peptide design: incorporation into helices

Incorporation of easily available achiral ω‐amino acid residues into an oligopeptide results in substitution of amide bonds by polymethylene units of an aliphatic chain, thereby providing a convenient strategy for constructing a peptidomimetic. The central Gly‐Gly segment of the helical octapeptide Boc‐Leu‐Aib‐Val‐Gly‐Gly‐Leu‐Aib‐Val‐Ome(1) has been replaced by δ‐amino‐valeric acid (δ‐Ava) residue in the newly designed peptide Boc‐Leu‐Aib‐Val‐δ‐Ava‐Leu‐Aib‐Val‐OMe(2). 1 H‐nmr results clearly suggest that in the apolar solvent CDCl 3 , the δ‐Ava residue is accommodated into a folded helical conformation, stabilized by successive hydrogen bonds involving the NH groups of Val(3), δ‐Ava(4), and Leu(5). The δ‐Ava residue must adopt a gauche‐gauche‐trans‐gauche‐gauche conformation along the central polymethylene unit of the aliphatic segment, a feature seen in an energy‐minimized model conformation based on nmr parameters. The absence of hydrogen bonding functionalities, however, limits the elongation of the helix. In fact, in CDCl 3 , the folded conformation consists of an N‐ terminal helix spanning residues 1–4, followed by a Type II β‐turn at residues 5 and 6, whereas in strongly solvating media like (CD 3 ) 2 SO, the unfolding of the N‐ terminal helix results in β‐turn conformations at Leu(1)‐Aib(2). The Type II β‐turn at the Leu(5)‐Aib(6) segment remains intact even in (CD 3 ) 2 SO. CD comparisons of peptides 1 and 2 reveal a “nonhelical” spectrum for 2 in 2,2,2‐trifluoroethanol. © 1996 John Wiley & Sons, Inc.