A homochiral L-Leu-L-Leu-Aib segment was incorporated into the N- or C-termini of left-handed (M) helical peptides (D-Leu-L-Leu-Aib)_n. We then investigated the preferred conformations of two sets of three peptides; i.e., Boc-L-Leu-L-Leu-Aib-(D-Leu-L-Leu-Aib)_n-OMe (n = 1: 1; 2: 2; 3: 3) and Boc-(D-Leu-L-Leu-Aib)_n-L-Leu-L-Leu-Aib-OMe (n = 1: 4; 2: 5; 3: 6), in solution and in the crystalline state. Nonapeptide 2 and dodecapeptide 3, each containing an N-terminal L-Leu-L-Leu-Aib segment, formed left-handed (M) helices as the preferred secondary structures in solution. In the crystalline state, nonapeptide 2 folded into an (M) α-helical structure. Peptides 4–6, each containing a C-terminal L-Leu-L-Leu-Aib segment, formed roughly equivalent amounts of right-handed (P) and (M) helices.

Two types of cationic cyclic α,α-disubstituted α-amino acids: Api (which possesses a lysine mimic side chain) and Api^C2Gu (which possesses an arginine mimic side chain), were developed. These amino acids were incorporated into an arginine-based peptide sequence [(l-Arg-l-Arg-dAA)₃: dAA=Api or Api^C2Gu], and the relationship between the secondary structures of the resulting peptides and their ability to pass through cell membranes was investigated. The peptide containing Api^C2Gu formed a stable α-helical structure and was more effective at penetrating cells than the nonhelical Arg nonapeptide (R₉). Furthermore, the peptide was able to deliver plasmid DNA into various types of cells in a highly efficient manner.