Moving on from clinical animal-derived surfactants to peptide-based synthetic pulmonary surfactant

Abstract

Research on lung surfactant has exerted a great impact on newborn respiratory care and significantly improved survival and outcome of preterm infants with respiratory distress syndrome (RDS) due to surfactant deficiency because of lung immaturity. Current clinical, animal-derived, surfactants are among the most widely tested compounds in neonatology. However, limited availability, high production costs, and ethical concerns about using animal-derived products constitute important limitations in their universal application. Synthetic lung surfactant offers a promising alternative to animal-derived surfactants by providing improved consistency, quality and purity, availability and scalability, ease of production and lower costs, acceptance, and safety for the treatment of neonatal RDS and other lung conditions. Third-generation synthetic surfactants built around surfactant protein B (SP-B) and C (SP-C) peptide mimics stand at the forefront of innovation in neonatal pulmonary medicine, while nasal continuous positive airway pressure (nCPAP) has become the standard noninvasive respiratory support for preterm infants. nCPAP can prevent the risk of chronic lung disease (bronchopulmonary dysplasia) and reduce lung injury by avoiding intubation and mechanical ventilation, is a relatively simple technique, and can be initiated safely and effectively in the delivery room. Combining nCPAP with noninvasive, preferably aerosol, delivery of synthetic lung surfactant promises to improve respiratory outcomes for preterm infants, especially in low- and middle-income countries.

Keywords: aerosol delivery; lung surfactant; nasal continuous positive airway pressure; peptide mimics; surfactant proteins B and C.

Figure 1.

Molecular illustration of the Super Mini B (SMB) peptide construct of the Saposin Surfactant Protein B (SP-B) derived from atomic coordinates deposited in the ModelArchive (https://modelarchive.org), accession code: ma-abz44. SMB has an amphipathic helix hairpin structure that emulates critical conformational elements of the Saposin fold associated with the parent SP-B protein (13). The N-terminal and C-terminal alpha helical domains of the peptide are highlighted in red with polar charged amino acids lysine and arginine in blue. The bend domain is shown in green with charged polar residues in blue while N-terminal phenylalanine of the insertion sequence is highlighted in orange. In the disulfide linked SMB peptide, cystine residues are in yellow showing the N-terminal – C-terminal covalent linked connectivity (Cys 8 – Cys 40; Cys 11 – Cys 34).

Figure 2.

Molecular illustration of the B-YL peptide construct of the Saposin Surfactant Protein B (SP-B) derived from atomic coordinates deposited in the ModelArchive (https://modelarchive.org), accession code: ma-vilb7–2. B-YL has an amphipathic helix hairpin structure that emulates critical conformational elements of the Saposin fold associated with the parent SP-B protein (28). The N-terminal and C-terminal alpha helical domains of the peptide are highlighted in red with polar charged amino acids lysine and arginine in blue. The bend domain is shown in green with charged polar residues in blue while N-terminal phenylalanine of the insertion sequence is highlighted in orange. The sulfur-free peptide B-YL has the helix hairpin structure stabilized by replacing all cysteine residues with tyrosine amino acids. These aromatic residue substitutions, highlighted in yellow, facilitate the non-covalent hydrophobic interaction of adjacent tyrosine aromatic rings that stabilize the helix-hairpin structure, thereby mimicking the disulfide connectivity of the SMB construct.

Figure 3.. Molecular illustration of the secondary structure prediction for the Canine SP-C Ion-Lock Protein.

Canine SP-C protein with phenylalanine substituted for cysteine-palmitic acid at amino acid position 4 in orange along with native sequence phenylalanine in position 5 and ion lock residue ion-lock pair E – K in magenta highlight at residues 20–24 in the hydrophobic poly-valine alpha helical amino acid sequence shown in blue. Bend and disordered domains are colored in green (35).