Synthesis and activity of a novel diether phosphonoglycerol in phospholipase-resistant synthetic lipid:peptide lung surfactants().
Synthesis and activity of a novel diether phosphonoglycerol in phospholipase-resistant synthetic lipid:peptide lung surfactants().
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抗磷脂酶合成脂质中新型二醚膦酰甘油的合成和活性：肽肺表面活性剂（）。
DOI：
10.1039/c1md00206f
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Notter,RobertH
中科院分区：
文献类型：
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作者：
Schwan,AdrianL;Singh,SuneelP;Davy,JasonA;Waring,AlanJ;Gordon,LarryM;Walther,FransJ;Wang,Zhengdong;Notter,RobertH
本文报道了一种新的抗磷脂酶的C16：0，C16：1二醚膦酰甘油的化学合成和纯化，其结构类似于内源性肺表面活性物质中的酯连接的阴离子磷脂酰甘油（PG）。研究了该二醚膦酰甘油（PG 1）的磷脂酶A2（PLA 2）抗性和在与Super Mini-B（S-MB）肽和DEPN-8（先前报道的二棕榈酰磷脂酰胆碱（DPPC，天然肺表面活性剂中的主要两性离子磷脂）的二醚膦酰脂质类似物）组合的合成外源性表面活性剂中的表面活性。活性实验测量了吸附和动态表面张力降低，因为这些表面行为在体内肺表面活性物质功能中具有已知的重要性。在色谱研究中，含有9：1 DEPN-8：PG 1 + 3% S-MB的合成表面活性剂对PLA 2的降解具有抗性，而小牛肺表面活性剂提取物（CLSE，牛临床表面活性剂Infasurf®的物质）被PLA 2显著降解。 与DEPN-8 + 3% S-MB相比，9：1 DEPN-8：PG 1 + 3% S-MB混合物在吸附和动态表面张力降低能力方面也具有小但一致的增加。 与这些表面活性增加一致，使用Protein Modeller、GROMACS力场和PyMOL的分子动力学模拟显示，含有DPPC和棕榈酰-油酰-PC（POPC）作为DEPN-8和PG 1的替代物的双层比单独的DPPC的双层更大程度地被S-MB肽穿透。这些结果表明，PG 1或相关的阴离子膦酰基-PG类似物可能在磷脂酶抗性合成表面活性剂中具有功能效用，所述磷脂酶抗性合成表面活性剂靶向急性肺损伤的形式，其中内源性表面活性剂由于先天性炎症反应中的磷脂酶活性而变得功能障碍。
This paper reports the chemical synthesis and purification of a novel phospholipase-resistant C16:0, C16:1 diether phosphonoglycerol with structural analogy to ester-linked anionic phosphatidylglycerol (PG) in endogenous pulmonary surfactant. This diether phosphonoglycerol (PG 1) is studied for phospholipase A2 (PLA2) resistance and for surface activity in synthetic exogenous surfactants combined with Super Mini-B (S-MB) peptide and DEPN-8, a previously-reported diether phosphonolipid analog of dipalmitoyl phosphatidylcholine (DPPC, the major zwitterionic phospholipid in native lung surfactant). Activity experiments measured both adsorption and dynamic surface tension lowering due to the known importance of these surface behaviors in lung surfactant function in vivo. Synthetic surfactants containing 9 : 1 DEPN-8:PG 1 + 3% S-MB were resistant to degradation by PLA2 in chromatographic studies, while calf lung surfactant extract (CLSE, the substance of the bovine clinical surfactant Infasurf®) was significantly degraded by PLA2. The 9 : 1 DEPN-8:PG 1 + 3% S-MB mixture also had small but consistent increases in both adsorption and dynamic surface tension lowering ability compared to DEPN-8 + 3% S-MB. Consistent with these surface activity increases, molecular dynamics simulations using Protein Modeller, GROMACS force-field, and PyMOL showed that bilayers containing DPPC and palmitoyl-oleoyl-PC (POPC) as surrogates of DEPN-8 and PG 1 were penetrated to a greater extent by S-MB peptide than bilayers of DPPC alone. These results suggest that PG 1 or related anionic phosphono-PG analogs may have functional utility in phospholipase-resistant synthetic surfactants targeting forms of acute pulmonary injury where endogenous surfactant becomes dysfunctional due to phospholipase activity in the innate inflammatory response.