Role of the hydrophobic face of amphipathic alpha-helical peptides in synthetic pulmonary surfactants.
The sequence requirements for the peptide component of a totally synthetic lung surfactant mixture were examined. A series of model amphipathic alpha-helical peptides (MAP) with six to 18 residues were synthesized by solid phase techniques, mixed with dipalmitoylphosphatidylcholine (DPPC) and tested for efficacy in an in vitro adult rat lung model. The most effective peptide in these mixtures contained 10 residues. Peptides containing eight and 14 residues were also highly active when mixed with DPPC in buffer, but a six-residue peptide was inactive. Longer peptides were active only when mixed with DPPC in trifluoroethanol before swelling in buffer; no other lipids were required to elicit high activity. Biologically effective peptides, when combined with DPPC, formed translucent mixtures that were significantly less turbid than ineffective mixtures, dramatically decreased the enthalpy of the main phase transition of DPPC and reduced the gamma min in the pulsating bubble surfactometer. Turbidity and minimal surface tensions were significantly correlated with activity in this series of peptides. These data show that effective synthetic lung surfactants may be prepared with mixtures of DPPC and idealized amphipathic alpha-helical peptides containing as few as eight to 10 residues. They lend further support to the hypothesis that amphipathic alpha-helical peptides with hydrophobic surface areas greater than approximately 6.5 nm2 in simple mixtures with DPPC are biologically active.
McLean
L R
LR
Marion Merrell Dow Research Institute, Cincinnati, Ohio.
Lewis
J E
JE
Hagaman
K A
KA
Owen
T J
TJ
Matthews
E R
ER
D000595:Amino Acid Sequence; D000818:Animals; D004285:Dogs; D005454:Fluorescence Polarization; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011663:Pulmonary Surfactants / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D011663:Pulmonary Surfactants