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Synthesis of small surfactant protein analogues has provided new insights in protein structure and function and its interaction with lipids.3-5 Walther et al. (reviewed in this issue) report how lipid mixtures affect the efficacy of surfactant protein analogues.6,7 Although simple lipid mixtures like dipalmitoyl phosphatidylcholine (DPPC): palmitoyl oleoyl PG (POPG) 70:30 (w/w) and DPPC:POPG:palmitic acid (PA) 69:22:9 (w/w/w) show excellent in vitro and in vivo surface activity with native surfactant proteins or selected synthetic peptides, use of a native lipid mixture with more unsaturated and less charged phospholipids, with cholesterol and only minor amounts of palmitic acid, further improved the efficacy of surfactant proteins and peptides.6 Synthetic lipid mixtures based on the composition of native surfactant may therefore be more appropriate in the formulation of synthetic surfactant peptides. Chang et al. (reviewed in this issue) report on a new class of phospholipase-resistant DPPC and PG (phosphono)lipids, such as the DPPC mimic DEPN-8, which offer the opportunity to design synthetic surfactants for use in ARDS where surfactant dysfunction prevails.8-10
Human SP-B contains 79 amino acids, α-helical structures in the amino- (N-) and carboxy- (C-) terminal domains, multiple polar residues interacting with phospholipids, and forms dimers and oligomers through intermolecular cysteine-linked sulfhydryl bridges.3,4 KL4 is a 21-amino acid peptide with an α-helical structure built with the hydrophobic amino acid leucine and the cationic amino acid lysine meant to mimic the functional structure of SP-B.11 The available data suggest that the KL4-based replacement surfactant lucinactant (Surfaxin®) is an effective synthetic surfactant, which, in contrast with natural surfactant, needs extensive preparation before it can be drawn up into a syringe for administration (Sinha et al., reviewed herein).12 The molecular mechanism by which KL4 interacts with lipids remains unclear.13 Waring et al. (reviewed herein) report how a novel, more advanced synthetic SP-B analogue called “Mini-B” (a disulfide-linked 34-amino acid construct based on the primary sequences of the N- and C-terminal domains of SP-B) exceeds the in vitro and in vivo activity of native SP-B.14
Human SP-C is smaller than SP-B (35 amino acids), and has two palmitoyl moieties and one α-helical structure. SP-C analogues have been produced by cloning (eg, recombinant human SP-C [rhSP-C] used in Venticute® surfactant) or peptide synthesis (eg, SP-Cff, SP-C33). 3-5,15,16 Production of SP-C analogues is complicated by the presence of the palmitoyl residues at the N-terminal domain and aggregation by transformation from a dominant α-helical conformation into β-amyloid structures that are not surface active. In rhSP-C and SP-Cff, two cysteines with palmitoyl residues have been replaced by phenylalanine. To minimize the loss of α-helix, Almlen et al. (reviewed herein) designed a shortened synthetic form of SP-C (SP-C33) with a number of different modifications. In SP-C33 the palmitoyl cysteine residues were replaced with serines, a leucine at position 14 with lysine, and a stretch of valine residues (positions 15–21 and 23–28) with an extended polyleucine sequence.17,18 Although SP-C33 mimics human SP-C function in vitro and in vivo experiments, SP-B is necessary to obtain alveolar stability at end-expiration in ventilated preterm rabbits.18
Wang et al. and Walther et al. (both reviewed herein) recently investigated combinations of native surfactant proteins, peptide analogues, and the phospholipase-resistant DPPC mimic DEPN-8.10,19,20 This work demonstrates the potential of these combinations to combat both surfactant deficiency and dysfunction.
Building upon the relatively limited functionality of first generation synthetic surfactants such as the KL4-surfactant lucinactant and the rhSP-C surfactant, recently developed novel SP-B and C peptides (such as Mini-B and SP-C33), formulated in novel phospholipase-resistant lipid mixtures, promise better surface activity under conditions of surfactant deficiency and dysfunction and offer more advanced surfactant treatment for a wider range of lung diseases.
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