Synthesis and surface activity of diether-linked phosphoglycerols: Potential applications for exogenous lung surfactants

Notter, Robert H.; Wang, Zhongyi; Wang, Zhengdong; Davy, Jason A.; Schwan, Adrian L.

doi:10.1016/j.bmcl.2006.09.083

Cited by 12 publications

(19 citation statements)

References 38 publications

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“…However, endogenous surfactant also contains anionic components (phosphatidylglycerol, phosphatidylinositol, and phosphatidylserine) capable of interacting with positively charged amino acid residues in surfactant apoproteins. We have recently defined the synthesis of novel diether PG analogs (two phosphoglycerols and one phosphonoglycerol compound) for potential combination with DEPN-8 or SO 2 -lipid in synthetic exogenous lung surfactants [52]. These PG analogs are all structurally resistant to phospholipases A 1 and A 2 , and the phosphonoglycerol is also resistant to phospholipase D. Initial surface activity assessments show that these PG analogs can increase the surface activity of DEPN-8 [52], and they are important candidates for further optimizing the lipid composition of synthetic surfactants containing DEPN-8 or SO 2 -lipid.…”

Section: Discussionmentioning

confidence: 99%

“…We have recently defined the synthesis of novel diether PG analogs (two phosphoglycerols and one phosphonoglycerol compound) for potential combination with DEPN-8 or SO 2 -lipid in synthetic exogenous lung surfactants [52]. These PG analogs are all structurally resistant to phospholipases A 1 and A 2 , and the phosphonoglycerol is also resistant to phospholipase D. Initial surface activity assessments show that these PG analogs can increase the surface activity of DEPN-8 [52], and they are important candidates for further optimizing the lipid composition of synthetic surfactants containing DEPN-8 or SO 2 -lipid. In addition to modifying lipid headgroups, fatty chains can also be altered to include one or more double bonds as opposed to the 16∶0 moieties in DEPN-8.…”

Section: Discussionmentioning

confidence: 99%

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Dynamic Surface Activity of a Fully Synthetic Phospholipase-Resistant Lipid/Peptide Lung Surfactant

et al. 2007

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BackgroundThis study examines the surface activity and resistance to phospholipase degradation of a fully-synthetic lung surfactant containing a novel diether phosphonolipid (DEPN-8) plus a 34 amino acid peptide (Mini-B) related to native surfactant protein (SP)-B. Activity studies used adsorption, pulsating bubble, and captive bubble methods to assess a range of surface behaviors, supplemented by molecular studies using Fourier transform infrared (FTIR) spectroscopy, circular dichroism (CD), and plasmon resonance. Calf lung surfactant extract (CLSE) was used as a positive control.ResultsDEPN-8+1.5% (by wt.) Mini-B was fully resistant to degradation by phospholipase A2 (PLA2) in vitro, while CLSE was severely degraded by this enzyme. Mini-B interacted with DEPN-8 at the molecular level based on FTIR spectroscopy, and had significant plasmon resonance binding affinity for DEPN-8. DEPN-8+1.5% Mini-B had greatly increased adsorption compared to DEPN-8 alone, but did not fully equal the very high adsorption of CLSE. In pulsating bubble studies at a low phospholipid concentration of 0.5 mg/ml, DEPN-8+1.5% Mini-B and CLSE both reached minimum surface tensions <1 mN/m after 10 min of cycling. DEPN-8 (2.5 mg/ml)+1.5% Mini-B and CLSE (2.5 mg/ml) also reached minimum surface tensions <1 mN/m at 10 min of pulsation in the presence of serum albumin (3 mg/ml) on the pulsating bubble. In captive bubble studies, DEPN-8+1.5% Mini-B and CLSE both generated minimum surface tensions <1 mN/m on 10 successive cycles of compression/expansion at quasi-static and dynamic rates.ConclusionsThese results show that DEPN-8 and 1.5% Mini-B form an interactive binary molecular mixture with very high surface activity and the ability to resist degradation by phospholipases in inflammatory lung injury. These characteristics are promising for the development of related fully-synthetic lipid/peptide exogenous surfactants for treating diseases of surfactant deficiency or dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dynamic Surface Activity of a Fully Synthetic Phospholipase-Resistant Lipid/Peptide Lung Surfactant

et al. 2007

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“…Ester-linked glycerophospholipids of the kind found in native surfactant are the primary lipids used in current synthetic exogenous surfactants. However, synthetic ether-linked lipids are now available that have direct structural analogy to lung surfactant lipids plus designed molecular behavior that enhances adsorption and spreading while maintaining very high dynamic surface tension lowering in surface films (e.g., [71,[205][206][207][208][209][210][211]). Moreover, such lipids have structural features making them resistant to phospholipases such as phospholipase A 2 , which has been implicated in the pathology of ALI/ARDS [65,[212][213][214][215][216][217][218].…”

Section: Examples Of Research On New Synthetic Exogenous Surfactamentioning

confidence: 99%

“…Phospholipase-induced degradation of lung surfactant glycerophospholipids not only reduces the concentration of active components, but also generates reaction products such as lysophosphatidylcholine and fluid free fatty acids that can further decrease surface activity by interacting biophysically with remaining surfactant at the alveolar interface [55,59,70]. Synthetic exogenous surfactants containing such phosphonolipids combined with purified surfactant proteins or synthetic peptides have very high overall surface activity plus an ability to resist phospholipases in ALI/ARDS [71,[208][209][210][211]219]. On-going basic research is continuing to design and synthesize peptides related to SP-B and other surfactant proteins for use in highly-active fully-synthetic exogenous surfactants in combination with either normal glycerophospholipids or phospholipase-resistant analogs.…”

Section: Examples Of Research On New Synthetic Exogenous Surfactamentioning

confidence: 99%

Surfactant for Pediatric Acute Lung Injury

Willson¹,

Chess²,

Notter³

2008

Pediatric Clinics of North America

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SynopsisThis article reviews exogenous surfactant therapy and its use in mitigating acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) in infants, children, and adults. Biophysical and animal research documenting surfactant dysfunction in ALI/ARDS is described, and the scientific rationale for treatment with exogenous surfactant is discussed. Major emphasis is on reviewing clinical studies of surfactant therapy in pediatric and adult patients with ALI/ARDS. Particular advantages from surfactant therapy in direct pulmonary forms of these syndromes are described. Also discussed are additional factors affecting the efficacy of exogenous surfactants in ALI/ARDS, including the multifaceted pathology of inflammatory lung injury, the effectiveness of surfactant delivery in injured lungs, and composition-based activity differences among clinical exogenous surfactant preparations.

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“…Curstedt and Johansson [8] have succinctly reviewed earlier work on the development of synthetic surfactant preparations for biomedical applications. More recently, substantial progress has also been made in the testing of novel synthetic lipids for use in surfactant preparations [9][10][11] . Here, we discuss our latest work on the design and testing of various peptides based on the structures of SP-B and SP-C, with the aim of developing fully synthetic mixtures of SP-B and SP-C analogues and lipids for use in both neonatal RDS and patients with ARDS.…”

Section: Introductionmentioning

confidence: 99%

Hydrophobic Surfactant Proteins and Their Analogues

et al. 2007

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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.

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Synthesis and surface activity of diether-linked phosphoglycerols: Potential applications for exogenous lung surfactants

Cited by 12 publications

References 38 publications

Dynamic Surface Activity of a Fully Synthetic Phospholipase-Resistant Lipid/Peptide Lung Surfactant

Dynamic Surface Activity of a Fully Synthetic Phospholipase-Resistant Lipid/Peptide Lung Surfactant

Surfactant for Pediatric Acute Lung Injury

Hydrophobic Surfactant Proteins and Their Analogues

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