Amphipathic alpha-helical peptides based on surfactant apoprotein SP-A.
Three peptides based on the putative amphipathic helical region of the major pulmonary surfactant apoprotein (SP-A) were synthesized by solid-phase techniques, mixed with DPPC and tested for efficacy as lung surfactants in an in vitro adult rat lavaged lung model. The peptides correspond to residues 81-102 (SP-A81-102) and 78-101 (SP-A78-101) of the native human sequence and an analog with increased hydrophobicity, Leu84,90SP-A78-101. Neither native sequence was effective in simple mixtures with DPPC. However, substitution of leucine residues for Asp84 and Thr90 of SP-A81-102 yielded a peptide which was active in mixtures with DPPC, restoring quasi-static lung compliance to 90% of the unlavaged value. In the absence of peptide, DPPC had no effect on the P-V curve of the lavaged lung. The activity of the Leu84,90 analog correlated with an increased amphipathic alpha-helical potential and an improvement in several predictive parameters for lipid-binding. The similarities between this active peptide and other active amphipathic alpha-helical peptides lend support to the hypothesis that amphipathic alpha-helical potential and the size of the hydrophobic face are critical for functional synthetic surfactant peptides in simple mixtures with dipalmitoylphosphatidylcholine.
McLean
L R
LR
Marion Merrell Dow Research Institute, Cincinnati, OH 45215.
Lewis
J E
JE
Hagaman
K A
KA
Owen
T J
TJ
Jackson
R L
RL
D015060:1,2-Dipalmitoylphosphatidylcholine; D000595:Amino Acid Sequence; D000818:Animals; D001059:Apoproteins / Q000737:chemistry* / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants / Q000737:chemistry* / Q000378:metabolism; D051381:Rats
D001059:Apoproteins; D010455:Peptides; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; C046616:pulmonary surfactant apoprotein; D015060:1,2-Dipalmitoylphosphatidylcholine