A model for the structure and mechanism of action of pulmonary surfactant protein B

Olmeda, Bárbara; García‐Álvarez, Begoña; Gómez, Manuel J.; Martínez-Calle, Marta; Cruz, Antonio; Pérez‐Gil, Jesús

doi:10.1096/fj.15-273458

Cited by 54 publications

(65 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such covalent attachments to the peptide scaffold may make the peptides more resistant to classical surfactant inhibitors including albumin [96]. The recent finding that native SP-B forms higher-ordered ring structures composed of 5 or 6 covalent dimers that may profoundly influence surface properties [97] should certainly be considered in future design strategies.…”

Section: New Sp-b Peptide Design Strategiesmentioning

confidence: 99%

Design of Surfactant Protein B Peptide Mimics Based on the Saposin Fold for Synthetic Lung Surfactants

2016

View full text Add to dashboard Cite

Surfactant protein (SP)-B is a 79-residue polypeptide crucial for the biophysical and physiological function of endogenous lung surfactant. SP-B is a member of the saposin or saposin-like proteins (SAPLIP) family of proteins that share an overall three-dimensional folding pattern based on secondary structures and disulfide connectivity and exhibit a wide diversity of biological functions. Here, we review the synthesis, molecular biophysics and activity of synthetic analogs of saposin proteins designed to mimic those interactions of the parent proteins with lipids that enhance interfacial activity. Saposin proteins generally interact with target lipids as either monomers or multimers via well-defined amphipathic helices, flexible hinge domains, and insertion sequences. Based on the known 3D-structural motif for the saposin family, we show how bioengineering techniques may be used to develop minimal peptide constructs that maintain desirable structural properties and activities in biomedical applications. One important application is the molecular design, synthesis and activity of Saposin mimics based on the SP-B structure. Synthetic lung surfactants containing active SP-B analogs may be potentially useful in treating diseases of surfactant deficiency or dysfunction including the neonatal respiratory distress syndrome and acute lung injury/acute respiratory distress syndrome.

show abstract

Section: New Sp-b Peptide Design Strategiesmentioning

confidence: 99%

Design of Surfactant Protein B Peptide Mimics Based on the Saposin Fold for Synthetic Lung Surfactants

2016

View full text Add to dashboard Cite

show abstract

“…Although both S-MB DATK and SP-Css ion-lock 1 effectively reduce surface tension and the combination further enhances surface activity, the main surface tension lowering effect is produced by the SP-B analog. This dominant SP-B effect might be explained by the recent finding that native SP-B forms higher-ordered ring structures composed of 5 or 6 covalent dimers that may profoundly influence surface properties (Olmeda, Garcia-Álvarez & Pérez-Gil, 2013; Olmeda et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Synthetic lung surfactants containing SP-B and SP-C peptides plus novel phospholipase-resistant lipids or glycerophospholipids

Notter

Gupta

Schwan

et al. 2016

PeerJ

View full text Add to dashboard Cite

BackgroundThis study examines the biophysical and preclinical pulmonary activity of synthetic lung surfactants containing novel phospholipase-resistant phosphonolipids or synthetic glycerophospholipids combined with Super Mini-B (S-MB) DATK and/or SP-Css ion-lock 1 peptides that replicate the functional biophysics of surfactant proteins (SP)-B and SP-C. Phospholipase-resistant phosphonolipids used in synthetic surfactants are DEPN-8 and PG-1, molecular analogs of dipalmitoyl phosphatidylcholine (DPPC) and palmitoyl-oleoyl phosphatidylglycerol (POPG), while glycerophospholipids used are active lipid components of native surfactant (DPPC:POPC:POPG 5:3:2 by weight). The objective of the work is to test whether these novel lipid/peptide synthetic surfactants have favorable preclinical activity (biophysical, pulmonary) for therapeutic use in reversing surfactant deficiency or dysfunction in lung disease or injury.MethodsSurface activity of synthetic lipid/peptide surfactants was assessed in vitro at 37 °C by measuring adsorption in a stirred subphase apparatus and dynamic surface tension lowering in pulsating and captive bubble surfactometers. Shear viscosity was measured as a function of shear rate on a Wells-Brookfield micro-viscometer. In vivo pulmonary activity was determined by measuring lung function (arterial oxygenation, dynamic lung compliance) in ventilated rats and rabbits with surfactant deficiency/dysfunction induced by saline lavage to lower arterial PO2 to <100 mmHg, consistent with clinical acute respiratory distress syndrome (ARDS).ResultsSynthetic surfactants containing 5:3:2 DPPC:POPC:POPG or 9:1 DEPN-8:PG-1 combined with 3% (by wt) of S-MB DATK, 3% SP-Css ion-lock 1, or 1.5% each of both peptides all adsorbed rapidly to low equilibrium surface tensions and also reduced surface tension to ≤1 mN/m under dynamic compression at 37 °C. However, dual-peptide surfactants containing 1.5% S-MB DATK + 1.5% SP-Css ion-lock 1 combined with 9:1 DEPN-8:PG-1 or 5:3:2 DPPC:POPC:POPG had the greatest in vivo activity in improving arterial oxygenation and dynamic lung compliance in ventilated animals with ARDS. Saline dispersions of these dual-peptide synthetic surfactants were also found to have shear viscosities comparable to or below those of current animal-derived surfactant drugs, supporting their potential ease of deliverability by instillation in future clinical applications.DiscussionOur findings support the potential of dual-peptide synthetic lipid/peptide surfactants containing S-MB DATK + SP-Css ion-lock 1 for treating diseases of surfactant deficiency or dysfunction. Moreover, phospholipase-resistant dual-peptide surfactants containing DEPN-8/PG-1 may have particular applications in treating direct forms of ARDS where endogenous phospholipases are present in the lungs.

show abstract

“…Other proposed models suggest that SP‐B forms bigger structures composed of oligomers of dimers. These complexes may form rings that can facilitate the reorganization and movement of phospholipids between membranes .…”

Section: Structural and Functional Properties Of Sp‐bmentioning

confidence: 99%

Synthetic surfactants with SP‐B and SP‐C analogues to enable worldwide treatment of neonatal respiratory distress syndrome and other lung diseases

Johansson

Curstedt

2018

J Intern Med

View full text Add to dashboard Cite

Treatment of neonatal respiratory distress syndrome (RDS) using animal‐derived lung surfactant preparations has reduced the mortality of handling premature infants with RDS to a 50th of that in the 1960s. The supply of animal‐derived lung surfactants is limited and only a part of the preterm babies is treated. Thus, there is a need to develop well‐defined synthetic replicas based on key components of natural surfactant. A synthetic product that equals natural‐derived surfactants would enable cost‐efficient production and could also facilitate the development of the treatments of other lung diseases than neonatal RDS. Recently the first synthetic surfactant that contains analogues of the two hydrophobic surfactant proteins B (SP‐B) and SP‐C entered clinical trials for the treatment of neonatal RDS. The development of functional synthetic analogues of SP‐B and SP‐C, however, is considerably more challenging than anticipated 30 years ago when the first structural information of the native proteins became available. For SP‐B, a complex three‐dimensional dimeric structure stabilized by several disulphides has necessitated the design of miniaturized analogues. The main challenge for SP‐C has been the pronounced amyloid aggregation propensity of its transmembrane region. The development of a functional non‐aggregating SP‐C analogue that can be produced synthetically was achieved by designing the amyloidogenic native sequence so that it spontaneously forms a stable transmembrane α‐helix.

show abstract

A model for the structure and mechanism of action of pulmonary surfactant protein B

Cited by 54 publications

References 73 publications

Design of Surfactant Protein B Peptide Mimics Based on the Saposin Fold for Synthetic Lung Surfactants

Design of Surfactant Protein B Peptide Mimics Based on the Saposin Fold for Synthetic Lung Surfactants

Synthetic lung surfactants containing SP-B and SP-C peptides plus novel phospholipase-resistant lipids or glycerophospholipids

Synthetic surfactants with SP‐B and SP‐C analogues to enable worldwide treatment of neonatal respiratory distress syndrome and other lung diseases

Contact Info

Product

Resources

About