Abstract
BackgroundOptimal functionality of synthetic lung surfactant for treatment of respiratory distress syndrome in preterm infants largely depends on the quality and quantity of the surfactant protein B (SP-B) peptide mimic and the lipid mixture. B-YL peptide is a 41-residue sulfur-free SP-B mimic with its cysteine and methionine residues replaced by tyrosine and leucine, respectively, to enhance its oxidation resistance.AimTesting the structural and functional stability of the B-YL peptide in synthetic surfactant lipids after long-term storage.MethodsThe structural and functional properties of B-YL peptide in surfactant lipids were studied using three production runs of B-YL peptides in synthetic surfactant lipids. Each run was held at 5 °C ambient temperature for three years and analyzed with structural and computational techniques, i.e., MALDI-TOF mass spectrometry, ATR-Fourier Transform Infrared Spectroscopy (ATR-FTIR), secondary homology modeling of a preliminary B-YL structure, and tertiary Molecular Dynamic simulations of B-YL in surfactant lipids, and with functional methods, i.e., captive bubble surfactometry (CBS) and retesting in vivo surface activity in surfactant-deficient young adult rabbits.ResultsMALDI-TOF mass spectrometry showed no degradation of the B-YL peptide as a function of stored time. ATR-FTIR studies demonstrated that the B-YL peptide still assumed stable alpha-helical conformations in synthetic surfactant lipids. These structural findings correlated with excellent in vitro surface activity during both quasi-static and dynamic cycling on CBS after three years of cold storage and in vivo surface activity of the aged formulations with improvements in oxygenation and dynamic lung compliance approaching those of the positive control surfactant Curosurf®.ConclusionsThe structure of the B-YL peptide and the in vitro and in vivo functions of the B-YL surfactant were each maintained after three years of refrigeration storage.
Highlights
Optimal functionality of synthetic lung surfactant for treatment of respiratory distress syndrome in preterm infants largely depends on the quality and quantity of the surfactant protein B (SP-B) peptide mimic and the lipid mixture
The structure of the B-YL peptide and the in vitro and in vivo functions of the B-YL surfactant were each maintained after three years of refrigeration storage
A synthetic surfactant preparation composed of the SP-B peptide mimic Super Mini-B (SMB) [5] and chemically synthesized synthetic phospholipids underwent chemical changes when stored for an extended period of time [6]
Summary
Optimal functionality of synthetic lung surfactant for treatment of respiratory distress syndrome in preterm infants largely depends on the quality and quantity of the surfactant protein B (SP-B) peptide mimic and the lipid mixture. Surfactant dispersions derived from extraction of porcine or bovine lung lavage show both degradation of the protein amino acid residues and conformational structure as a function of time [3, 4] Such changes in primary and secondary structure correlate with loss of in vitro and in vivo surface activity that attenuates the efficacy of the dispersion used for surfactant therapy. A synthetic surfactant preparation composed of the SP-B peptide mimic Super Mini-B (SMB) [5] and chemically synthesized synthetic phospholipids underwent chemical changes when stored for an extended period of time [6] To minimize these changes in the SMB peptide and its secondary conformation and to optimize its surface activity, we developed a sulfur-free peptide B-YL by substituting cysteine residues in SMB with tyrosine and eliminating the need for oxidative formation of the disulfide linkages to stabilize the peptide structure [7]. We investigate the structure, function and stability of this B-YL peptide in surfactant lipids after prolonged refrigerator storage
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