Hydrophobic Surfactant Proteins and Their Analogues

Abstract

Lung surfactant is a complex mixture of phospholipids and four surfactant-associated proteins (SP-A, SP-B, SP-C and SP-D). Its major function in the lung alveolus is to reduce surface tension at the air-water interface in the terminal airways by the formation of a surface-active film enriched in surfactant lipids, hence preventing cellular collapse during respiration. Surfactant therapy using bovine or porcine lung surfactant extracts, which contain only polar lipids and native SP-B and SP-C, has dramatically improved the therapeutic outcomes of preterm infants with respiratory distress syndrome (RDS). One important goal of surfactant researchers is to replace animal-derived therapies with fully synthetic preparations based on SP-B and SP-C, produced by recombinant technology or peptide synthesis, and reconstituted with selected synthetic lipids. Here, we review recent research developments with peptide analogues of SP-B and SP-C, designed using either the known primary sequence and three-dimensional (3D) structure of the native proteins or, alternatively, the known 3D structures of closely homologous proteins. Such SP-B and SP-C mimics offer the possibility of studying the mechanisms of action of the respective native proteins, and may allow the design of optimized surfactant formulations for specific pulmonary diseases (e.g., acute lung injury (ALI) or acute respiratory distress syndrome (ARDS)). These synthetic surfactant preparations may also be a cost-saving therapeutic approach, with better quality control than may be obtained with animal-based treatments.

European Consensus Guidelines on the Management of Neonatal Respiratory Distress Syndrome in Preterm Infants - 2013 Update

“…Overall there is a survival advantage when a 200 mg/kg dose of poractant alfa is compared with 100 mg/kg of beractant or 100 mg/kg poractant alfa to treat RDS [44] . New generation synthetic surfactants containing surfactant protein analogues appear to work better than older synthetic surfactants and are currently undergoing evaluation in clinical trials [63,64] . Surfactant preparations containing budesonide have also been developed and are undergoing evaluation to determine if the addition of steroid will reduce the incidence of BPD [65] .…”

The Future of Exogenous Surfactant Therapy

“…In addition, several synthetic exogenous surfactants are under clinical study and laboratory research. [16][17][18][19][20][21][22][23][24] …”

“…44 Recent advances in molecular bioengineering and peptide chemistry also provide the potential to design new even more active synthetic lung surfactants, and several approaches are being studied. 19,20,24,45 These include fully synthetic surfactants bioengineered to contain peptides that incorporate functionally crucial structural regions in human SP-B, such as the highly active super mini-B peptide recently reported by Waring and colleagues. 22 New synthetic surfactants can also contain peptide components that incorporate active regions of other human surfactant apoproteins in combination with SP-B peptides.…”

Surfactant for Pediatric Acute Lung Injury

“…Surfaxin® (KL4) [87,107,123,[189][190][191][192][193][194][195] and Venticute® (recombinant SPC surfactant) [26,[196][197][198][199][200][201] are two current examples of the first of these approaches (Table 3). However, the 21 amino acid KL4 peptide is only a very rough structural analog to native SP-B, and advances in peptide molecular modeling and synthesis technology support the feasibility of preparing new SP-B peptides with significantly greater sequence and molecular folding specificity, and correspondingly higher activity ( [202][203][204] for review). The development of new synthetic SP-B peptides is particularly important for optimal synthetic exogenous surfactants given the greater activity of SP-B compared to SP-C in native surfactant noted earlier [118,[176][177][178][179][180][181][182][183][184].…”