Lipid membrane permeability of modified c[D-Pen2, D-Pen5]enkephalin peptides.
Permeability coefficients of a series of analogues of a potent opioid peptide, c[D-Pen2, D-Pen5]enkephalin, were measured in a model membrane system. The analogues included hydrophobic amino acid substitutions on position 3. Liposomes of a mixed composition consisting of zwitterionic lipids and cholesterol served as the model membranes. The obtained permeability coefficients range between 0.38 x 10(-12) and 2.9 x 10(-12) cm/s. These data were correlated with the hydrophobicity scale of Nozaki and Tanford (J. Biol. Chem. 246, 1971, 2211-2217) (correlation coefficient = 0.9933) and with determinations of lipid order perturbation by differential scanning calorimetry (correlation coefficient = -0.9779). The reasonably good correlation obtained within the family of analogues substituted on position 3 (Gly, Ala, Leu, Phe) indicates 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 follow the observed trend, showing stronger lipid perturbation and lower permeability compared to the Phe3 analog. This observation demonstrates that each class of peptide modifications requires a new basis of permeability analysis and predictions.
Ramaswami
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V
Carl S. Marvel Laboratories, Department of Chemistry, University of Arizona, Tucson, USA.
Zhu
X
X
Romanowski
M
M
Haaseth
R C
RC
Misicka
A
A
Lipkowski
A W
AW
Hruby
V J
VJ
O'Brien
D F
DF
D002152:Calorimetry, Differential Scanning / Q000379:methods; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry; D008567:Membranes, Artificial; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D010539:Permeability; D013329:Structure-Activity Relationship
D004745:Enkephalins; D008051:Lipid Bilayers; D008081:Liposomes; D008567:Membranes, Artificial; D010455:Peptides; D020881:Enkephalin, D-Penicillamine (2,5)-