McLean L R, Lewis J E, Hagaman K A, Owen T J, Matthews E R
Marion Merrell Dow Research Institute, Cincinnati, Ohio.
J Pharmacol Exp Ther. 1993 Aug;266(2):551-6.
The sequence requirements for the peptide component of a totally synthetic lung surfactant mixture were examined. A series of model amphipathic alpha-helical peptides (MAP) with six to 18 residues were synthesized by solid phase techniques, mixed with dipalmitoylphosphatidylcholine (DPPC) and tested for efficacy in an in vitro adult rat lung model. The most effective peptide in these mixtures contained 10 residues. Peptides containing eight and 14 residues were also highly active when mixed with DPPC in buffer, but a six-residue peptide was inactive. Longer peptides were active only when mixed with DPPC in trifluoroethanol before swelling in buffer; no other lipids were required to elicit high activity. Biologically effective peptides, when combined with DPPC, formed translucent mixtures that were significantly less turbid than ineffective mixtures, dramatically decreased the enthalpy of the main phase transition of DPPC and reduced the gamma min in the pulsating bubble surfactometer. Turbidity and minimal surface tensions were significantly correlated with activity in this series of peptides. These data show that effective synthetic lung surfactants may be prepared with mixtures of DPPC and idealized amphipathic alpha-helical peptides containing as few as eight to 10 residues. They lend further support to the hypothesis that amphipathic alpha-helical peptides with hydrophobic surface areas greater than approximately 6.5 nm2 in simple mixtures with DPPC are biologically active.
对全合成肺表面活性剂混合物中肽成分的序列要求进行了研究。通过固相技术合成了一系列含有6至18个残基的模型两亲性α-螺旋肽（MAP），将其与二棕榈酰磷脂酰胆碱（DPPC）混合，并在体外成年大鼠肺模型中测试其功效。这些混合物中最有效的肽含有10个残基。含有8个和14个残基的肽在缓冲液中与DPPC混合时也具有高活性，但6个残基的肽没有活性。较长的肽仅在缓冲液中溶胀前在三氟乙醇中与DPPC混合时才有活性；引发高活性不需要其他脂质。具有生物学活性的肽与DPPC结合时，形成半透明混合物，其浊度明显低于无活性的混合物，显著降低了DPPC主相变的焓，并降低了脉动气泡表面张力仪中的最小表面张力。在这一系列肽中，浊度和最小表面张力与活性显著相关。这些数据表明，有效的合成肺表面活性剂可以用DPPC和含有低至8至10个残基的理想化两亲性α-螺旋肽的混合物制备。它们进一步支持了以下假设：在与DPPC的简单混合物中，疏水表面积大于约6.5 nm2的两亲性α-螺旋肽具有生物学活性。
