The C-and N-terminal residues of synthetic heptapeptide ion channels influence transport efficacy through phospholipid bilayers

Abstract

The synthetic peptide, R₂N-COCH₂OCH₂CO-Gly-Gly-Gly-Pro-Gly-Gly-Gly-OR′, was shown to be selective for Cl⁻ over K⁺ when R is n-octadecyl and R′ is benzyl. Nineteen heptapeptides have now been prepared in which the N-terminal and C-terminal residues have been varied. All of the N-terminal residues are dialkyl but the C-terminal chains are esters, 2° amides, or 3° amides. The compounds having varied N-terminal anchors and C-terminal benzyl groups are as follows: 1, R = n-propyl; 2, R = n-hexyl; 3, R = n-octyl; 4, R = n-decyl; 5, R = n-dodecyl; 6, R = n-tetradecyl; 7, R = n-hexadecyl; 8, R = n-octadecyl. Compounds 9–19 have R = n-octadecyl and C-terminal residues as follows: 9, OR′ = OCH₂CH₃; 10, OR′ = OCH(CH₃)₂; 11, OR′ = O(CH₂)₆CH₃; 12, OR′ = OCH₂–c-C₆H₁₁; 13, OR′ = O(CH₂)₉CH₃; 14, OR′ = O(CH₂)₁₇CH₃; 15, NR′₂ = N[(CH₂)₆CH₃]₂; 16, NHR′ = NH(CH₂)₉CH₃; 17, NR′₂ = N[(CH₂)₉CH₃]₂; 18, NHR′ = NH(CH₂)₁₇CH₃; 19, NR′₂ = N[(CH₂)₁₇CH₃]₂. The highest anion transport activities were observed as follows. For the benzyl esters whose N-terminal residues were varied, i.e.1–8, compound 3 was most active. For the C₁₈ anchored esters 10–14, n-heptyl ester 11 was most active. For the C₁₈ anchored, C-terminal amides 15–19, di-n-decylamide 17 was most active. It was concluded that both the C-and N-terminal anchors were important for channel function in the bilayer but that activity was lost unless only one of the two anchoring groups was dominant.