Treatment of Respiratory Distress Syndrome with Single Recombinant Polypeptides that Combine Features of SP-B and SP-C.

Oihana Basabe-Burgos,Anna Rising,Tore Curstedt,Jan Johansson Jan Johansson,Michael Landreh

doi:10.1021/acschembio.1c00816

Oihana Basabe-Burgos, Anna Rising + Show 3 more

Open Access

https://doi.org/10.1021/acschembio.1c00816

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Abstract

Treatment of respiratory distress syndrome (RDS) with surfactant replacement therapy in prematurely born infants was introduced more than 30 years ago; however, the surfactant preparations currently in clinical use are extracts from animal lungs. A synthetic surfactant that matches the currently used nature-derived surfactant preparations and can be produced in a cost-efficient manner would enable worldwide treatment of neonatal RDS and could also be tested against lung diseases in adults. The major challenge in developing fully functional synthetic surfactant preparations is to recapitulate the properties of the hydrophobic lung surfactant proteins B (SP-B) and SP-C. Here, we have designed single polypeptides that combine properties of SP-B and SP-C and produced them recombinantly using a novel solubility tag based on spider silk production. These Combo peptides mixed with phospholipids are as efficient as nature-derived surfactant preparations against neonatal RDS in premature rabbit fetuses.

Highlights

Pulmonary surfactant is essential for normal respiration by increasing lung compliance and preventing alveolar collapse and it contributes to lung host defense
The Combo peptides were designed by fusing an surfactant proteins B (SP-B) analogue, a linker, and an SP-C analogue into one polypeptide (Figure 1a)
The SP-C33Leu analogue was included in all Combo peptides, since synthetic or recombinant SPC33Leu can be used to formulate synthetic surfactants that are efficient in animal models of neonatal respiratory distress syndrome (RDS) as well as ARDS and can be produced in high amounts.[38,40−43] All Combo peptides have an SP-B analogue with two predicted α-helices with similarities to Mini-BLeu, either without (Combo peptides A, C, and D) or with two (Combo peptides B and E) Cys residues

Summary

Introduction

Pulmonary surfactant is essential for normal respiration by increasing lung compliance and preventing alveolar collapse and it contributes to lung host defense. An N-terminal sequence analysis of the upper SDS-PAGE band, migrating around 12 kDa, obtained after Sephadex LH60 chromatography of Combo peptide E (Figure 2d), using Edman degradation for 10 cycles, gave the amino acid sequence LXLXRALIRR, where X denotes no identified residue.

Results

Conclusion