OMEGA-AMINO ACIDS IN PEPTIDE DESIGN - INCORPORATION INTO HELICES

Incorporation of easily available achiral omega-amino acid residues in to an oligopeptide results in substitution of amide bonds by polymethy lene units of an aliphatic chain, thereby providing a convenient strat egy 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 The central Gly-Gly segment of the helical octapeptide Boc-Leu-Aib-Val-Gly-Gly-Leu-Aib-Val-OMe(1) has been replaced by delta-amino-valeric acid (delta-Ava) residue in the newly designed peptide Boc-Leu-Aib-Val-delta-Ava-Leu-Aib-Val-OMe(2). H -1-nmr results clearly suggest that in the apolar solvent CDCl3, the d elta-Ava residue is accommodated into a folded helical conformation, s tabilized by successive hydrogen bonds involving the NH groups of Val( 3), delta-Ava(4), and Leu(5). The delta-Ava residue must adopt a gauch e-gauche-trans-gauche-gauche conformation along the central polymethyl ene unit of the aliphatic segment, a feature seen in an energy-minimiz ed model conformation based on nmr parameters. The absence of hydrogen bonding functionalities, however, limits the elongation of the helix. In fact, in CDCl3, the folded conformation consists of an N-terminal helix spanning residues 1-4, followed by a Type II beta-turn at residu es 5 and 6, whereas in strongly solvating media like (CD3)(2)SO, the u nfolding of the N-terminal helix results in beta-turn conformations at Leu(1)-Aib(2). The Type II beta-turn at the Leu(5)-Aib(6) segment rem ains intact even in (CD3)(2)SO. CD comparisons of peptides 1 and 2 rev eal a ''nonhelical'' spectrum for 2 in 2,2,2-trifluoroethanol. (C) 199 6 John Wiley & Sons, Inc.