Structural and Functional Importance of the C-Terminal Part of the Pulmonary Surfactant Polypeptide SP-C

Clercx, Anne; Vandenbussche, Guy; Curstedt, Tore; Johansson, Jan; Jörnvall, Hans; Ruysschaert, Jean‐Marie

doi:10.1111/j.1432-1033.1995.0465k.x

Cited by 16 publications

(19 citation statements)

References 53 publications

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“…This indicates that it is more important to capture the extreme hydrophobicity and highly helical structure of SP-C rather than its exact side chain chemistry, which is consistent with previous studies of peptide analogues 53 .…”

Section: Synthetic Sp-c Analoguessupporting

confidence: 89%

Biomimicry of Surfactant Protein C

2008

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CONSPECTUS Since the widespread use of exogenous lung surfactant to treat neonatal respiratory distress syndrome, premature infant survival and respiratory morbidity have dramatically improved. Despite the effectiveness of the animal-derived surfactant preparations, there still remain some concerns and difficulties associated with their use. This has prompted investigation into the creation of synthetic surfactant preparations. However, to date, no clinically used synthetic formulation is as effective as the natural material. This is largely because the previous synthetic formulations lacked analogues of the hydrophobic proteins of the lung surfactant system, SP-B and SP-C, which are critical functional constituents. As a result, recent investigation has turned towards the development of a new generation of synthetic, biomimetic surfactants that contain synthetic phospholipids along with a mimic of the hydrophobic protein portion of lung surfactant. In this Account, we detail our efforts in creating accurate mimics of SP-C for use in a synthetic surfactant replacement therapy. Despite SP-C’s seemingly simple structure, the predominantly helical protein is extraordinarily challenging to work with given its extreme hydrophobicity and structural instability, which greatly complicates the creation of an effective SP-C analogue. Drawing inspiration from Nature, two promising biomimetic approaches have led to the creation of rationally designed biopolymers that recapitulate many of SP-C’s molecular features. The first approach utilizes detailed SP-C structure-activity relationships and amino acid folding propensities to create a peptide-based analogue, SP-C33. In SP-C33, the problematic and metastable poly-valine helix is replaced with a structurally stable, poly-leucine helix and includes a well placed positive charge to prevent aggregation. SP-C33 is both structurally stable and eliminates the association propensity of the native protein. The second approach follows the same design considerations, but makes use of a non-natural, poly-N-substituted glycine or “peptoid” scaffold to circumvent the difficulties associated with SP-C. By incorporating unique, biomimetic side chains in a non-natural backbone, the peptoid mimic captures both SP-C’s hydrophobic patterning and helical secondary structure. Despite the differences in structure, both SP-C33 and the SP-C peptoid mimic capture many requisite features of SP-C. In a surfactant environment, these analogues also replicate many of the key surface activities necessary for a functional biomimetic surfactant therapy while overcoming the difficulties associated with the natural protein. With improved stability, greater production potential, and elimination of possible pathogenic contamination, these biomimetic surfactant formulations offer the potential not only to improve the treatment of respiratory distress syndrome, but also the opportunity to treat other respiratory-related disorders.

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Section: Synthetic Sp-c Analoguessupporting

confidence: 89%

Biomimicry of Surfactant Protein C

2008

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“…Such interactions are difficult to envision with the KL4 helical surface and orientation in a phospholipid bilayer now found, suggesting another mechanism of action for KL4 in pulmonary phospholipids. The secondary structure and transmembranous orientation of KL4 prompts investigation of its spreading properties in a lipid mixture, since another transmembrane helix (SP-C/BR) with a primary structure which is unrelated to any of the pulmonary surfactant proteins has significant effects on lipid spreading kinetics [20,26]. KL4 does accelerate the spreading of lipids at an air/water interface but it is less effective than both native SP-C and the SP-C/BR hybrid in this respect.…”

Section: Orientation Of Kla In a Phospholipid Bilayermentioning

confidence: 99%

“…interface Spreading kinetics of 2% (w/w) of KL4 in a DPPC/PG/PA 68:22:9 (by weight) mixture at an air/water interface was compared to that of native SP-C and SP-C/BR [20], both with transmembranous c~-helices in similar phospholipid mixtures [11,12,14,26]. KL4 is less efficient than native SP-C and SP-C/BR in accelerating the spreading of the lipid mixture and also reaches a lower surface pressure after 1 min (Fig.…”

Section: Effects Of Kl4 On the Spreading Of Lipids At An Air~watermentioning

confidence: 99%

The 21‐residue surfactant peptide (LysLeu₄)₄Lys(KL₄) is a transmembrane α‐helix with a mixed nonpolar/polar surface

et al. 1996

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The 21-residue peptide KLLLLKLLLLKLL-LLKLLLLK (KL4) has been synthesized and analyzed regarding its secondary structure and orientation in lipid environments. Fourier transform infrared and circular dichroism spectroscopy shows that the peptide exhibits approximately 80% a-helical content both in dodecylphosphocholine micelles and in 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/phosphatidylglycerol (PG) 7:3 (w/w) bilayers. The positively charged lysine residues are evenly distributed over the entire, otherwise nonpolar, circumference of the helix. This is in sharp contrast to the uneven distribution of polar and nonpolar residues in amphipathic helices. Fourier transform infrared spectroscopy of the peptide inserted in DPPC/PG bilayers shows that the helical axis is oriented parallel to the lipid acyl chains. These data do not support a previous hypothesis that the KL4 peptide interacts with peripheral parts of a phospholipid monolayer and mimics the pulmonary surfactant protein SP-B, which is composed of several amphipathic ¢x-helices. KL4 accelerates the spreading of phospholipid mixtures at an air/water interface but does so less efficiently than other transmembranous helical polypeptides studied.

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“…Human SP-C FGIPCCPVHLKRLLIVVVVVVLIVVVIVGALLMGL the N-terminal region supported that the a-helical structure determined in organic solvents exists in lipid detergents and phospholipid bilayers, making it most likely that it represents the structure of SP-C in native surfactant [110][111][112][113]. Importantly, the length of the entire SP-C a-helix determined in organic solvents (37 A), and of its central part that contains exclusively non-polar residues (23 A), perfectly matches the thickness of a fluid DPPC bilayer and its central part composed of non-polar fatty acyl chains respectively [111].…”

Section: Polypeptide Sequencementioning

confidence: 91%

“…In agreement with the strong preference for b-sheet structure of a polyVal sequence, synthetic replicas of SP-C form mainly b-sheet aggregates, which, when combined with synthetic phospholipids, show low surface activity in vitro [193]. A first indication how this obstacle could be circumvented came from the observation that replacing the polyVal transmembrane segment with the amino acid sequence of the second transmembrane helix of bacteriorhodopsin, which lacks sequence resemblance to SP-C, resulted in a hybrid peptide (SP-C/ BR, Table 2) with high a-helical content and good surface activity in vitro [110,193]. This suggested that the a-helical conformation of the transmembrane region as such, rather than the amino acid sequence, is of prime importance for the biological function of synthetic SP-C analogues [193].…”

Section: Development Of Sp-c Analoguesmentioning

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

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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.

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Structural and Functional Importance of the C-Terminal Part of the Pulmonary Surfactant Polypeptide SP-C

Cited by 16 publications

References 53 publications

Biomimicry of Surfactant Protein C

Biomimicry of Surfactant Protein C

The 21‐residue surfactant peptide (LysLeu₄)₄Lys(KL₄) is a transmembrane α‐helix with a mixed nonpolar/polar surface

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

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Structural and Functional Importance of the C-Terminal Part of the Pulmonary Surfactant Polypeptide SP-C

Cited by 16 publications

References 53 publications

Biomimicry of Surfactant Protein C

Biomimicry of Surfactant Protein C

The 21‐residue surfactant peptide (LysLeu4)4Lys(KL4) is a transmembrane α‐helix with a mixed nonpolar/polar surface

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

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The 21‐residue surfactant peptide (LysLeu₄)₄Lys(KL₄) is a transmembrane α‐helix with a mixed nonpolar/polar surface