New Synthetic Surfactant – How and When?

Curstedt, Tore; Johansson, Jan

doi:10.1159/000092871

Cited by 30 publications

(38 citation statements)

References 56 publications

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“…29 Basic science of the new synthetic surfactants Lucinactant is only one of many new synthetic surfactant preparations in various stages of development. 40 Lucinactant contains 2.7% KL4, DPPC/POPG in a ratio of 3:1 and 13.5% palmitic acid. It contains 30 mg phospholipids per ml and is suspended in buffer at pH 7.6 forming a gel until warmed to 44 1C.…”

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“…42 To date it has not been possible to synthesize SP-B as it has a complex structure and although KL4 has been described as an SP-B mimic it seems to form a transmembrane a-helix making it more likely to function as an SP-C mimic. 40 SP-C itself is very hydrophobic and especially in pure form is structurally very unstable. 40 Recombinant SP-C has been used in a commercially produced surfactant called Venticute.…”

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“…40 SP-C itself is very hydrophobic and especially in pure form is structurally very unstable. 40 Recombinant SP-C has been used in a commercially produced surfactant called Venticute. 43 This has 2% rSP-C, DPPC/POPG in a ratio of 7:3 and 5% palmitic acid.…”

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“…It contains 50 mg phospholipids per ml and is a liquid suspension. 40 rSP-C surfactant has been studied in adults with ARDS 43 but not in neonatal RDS. Another surfactant containing SP-C33 is currently being studied in Stockholm but no clinical trials have yet been reported.…”

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“…Another surfactant containing SP-C33 is currently being studied in Stockholm but no clinical trials have yet been reported. 40 This synthetic surfactant contains 2% SP-C33, DPPC/POPG in a 7:3 ratio but no palmitic acid. It is a liquid suspension and can be concentrated to 80 mg phospholipids per ml.…”

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Surfactants: past, present and future

2008

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In 1929 Kurt von Neergaard performed experiments suggesting the presence of pulmonary surfactant and its relevance to the newborn's first breath. Almost 25 years later, Richard Pattle, John Clements and Chris Macklin, each working on the effects of nerve gases on the lungs, contributed to the understanding of the physiology of pulmonary surfactant. About 5 years later Mary Ellen Avery and Jere Mead published convincing evidence that preterm neonates dying of hyaline membrane disease (respiratory distress syndrome, RDS) had a deficiency of pulmonary surfactant. The first trials of nebulized synthetic (protein-free) surfactant to prevent RDS were published soon after Patrick Bouvier Kennedy (son of President John F Kennedy) died of this disorder after treatment in Boston. These trials were unsuccessful; however, Goran Enhorning and Bengt Robertson in the early 1970s demonstrated that natural surfactants (containing proteins) were effective in an immature rabbit model of RDS. Soon after this Forrest Adams showed that a natural surfactant was also effective in an immature lamb model. Working with him was Tetsuro Fujiwara who 2 years later, after returning to Japan, published the seminal article reporting the responses of 10 preterm infants with RDS to a bolus of modified bovine surfactant. During the 1980s there were numerous randomized controlled trials of many different natural and synthetic surfactants, demonstrating reductions in pulmonary air leaks and neonatal mortality. Subsequently natural surfactants were shown to be superior to the protein-free synthetic products. Recently there have been a number of randomized trials comparing different natural surfactant preparations. Commercially available bovine surfactants may have similar efficacy but there is some evidence that a porcine surfactant used to treat RDS with an initial dose of 200 mg kg À1 is more effective than a bovine surfactant used in an initial dose of 100 mg kg -1 . Bovine and porcine surfactants have not been compared in trials of prophylaxis. Very recently a new synthetic surfactant with a surfactant protein mimic has been compared with other commercially available natural and synthetic surfactants in two trials. The new surfactant may be superior to one of the older protein-free synthetic surfactants but there is no evidence of its superiority over established natural products and it is currently not approved for clinical use. A number of other new synthetic surfactants have been tested in animal models or in treatment of adults with ARDS, but so far there have been no reports of treatment of neonatal RDS. Natural surfactants work best if given by a rapid bolus into the lungs but less invasive methods such as a laryngeal mask, pharyngeal deposition or rapid extubation to CPAP have showed promise. Unfortunately, delivery of surfactant by nebulization has so far been ineffective. Surfactant treatment has been tried in a number of other neonatal respiratory disorders but only infants with meconium aspiration seem to benefit although larger and mo...

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Surfactants: past, present and future

2008

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Helical side chain chemistry of a peptoid‐based SP‐C analogue: Balancing structural rigidity and biomimicry

2019

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Surfactant protein C (SP‐C) is an important constituent of lung surfactant (LS) and, along with SP‐B, is included in exogenous surfactant replacement therapies for treating respiratory distress syndrome (RDS). SP‐C's biophysical activity depends upon the presence of a rigid C‐terminal helix, of which the secondary structure is more crucial to functionality than precise side‐chain chemistry. SP‐C is highly sequence‐conserved, suggesting that the β‐branched, aliphatic side chains of the helix are also important. Nonnatural mimics of SP‐C were created using a poly‐N‐substituted glycine, or “peptoid,” backbone. The mimics included varying amounts of α‐chiral, aliphatic side chains and α‐chiral, aromatic side chains in the helical region, imparting either biomimicry or structural rigidity. Biophysical studies confirmed that the peptoids mimicked SP‐C's secondary structure and replicated many of its surface‐active characteristics. Surface activity was optimized by incorporating both structurally rigid and biomimetic side chain chemistries in the helical region indicating that both characteristics are important for activity. By balancing these features in one mimic, a novel analogue was created that emulates SP‐C's in vitro surface activity while overcoming many of the challenges related to natural SP‐C. Peptoid‐based analogues hold great potential for use in a synthetic, biomimetic LS formulation for treating RDS.

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