LIPID-MEMBRANE PERMEABILITY OF MODIFIED C[D-PEN(2), D-PEN(5)] ENKEPHALIN PEPTIDES

Permeability coefficients of a series of analogues of a potent opioid peptide, c[D-Pen(2), D-Pen(5)]enkephalin, were measured in a model mem brane system. The analogues included hydrophobic amino acid substituti ons on position 3. Liposomes of a mixed composition consisting of zwit terionic lipids and cholesterol served as the model membranes. The obt ained permeability coefficients range between 0.38 x 10(-12) and 2.9 x 10(-12) cm/s. These data were correlated with the hydrophobicity scal e of Nozaki and Tanford (J. Biol. Chem. 246, 1971, 2211-2217) (correla tion coefficient = 0.9933) and with determinations of lipid order pert urbation by differential scanning calorimetry (correlation coefficient = -0.9779). The reasonably good correlation obtained within the famil y of analogues substituted on position 3 (Gly, Ala, Leu, Phe) indicate s that changes in permeabilities are primarily related to increases in the partition coefficient of the peptide. However, Phe residue added on the N-terminal end of the peptide (position 0) does not appear to f ollow the observed trend, showing stronger lipid perturbation and lowe r permeability compared to the Phe(3) analog. This observation demonst rates that each class of peptide modifications requires a new basis of permeability analysis and predictions. (C) Munksgaard 1996.