Systematic Analysis of the Relationship among 3D Structure, Bioactivity, and Membrane Permeability of PF1171F, a Cyclic Hexapeptide with Paralyzing Effects on Silkworms
Systematic Analysis of the Relationship among 3D Structure, Bioactivity, and Membrane Permeability of PF1171F, a Cyclic Hexapeptide with Paralyzing Effects on Silkworms
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系统分析对蚕具有麻痹作用的环状六肽PF1171F的3D结构、生物活性和膜通透性之间的关系
DOI：
10.1021/acs.joc.7b01975
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发表时间：
2017
期刊：
影响因子：
3.6
通讯作者：
Doi Takayuki
中科院分区：
文献类型：
--
作者：
Masuda Yuichi;Tanaka Ren;Ganesan A.;Doi Takayuki
PF1171六肽是一类由真菌产生的环状六肽类化合物，对家蚕幼虫具有口服麻痹作用。为了阐明对生物活性起关键作用的六肽的结构特征，通过合成22个类似物，系统分析了生物利用度最高的多肽PF1171F的三维结构、生物活性和膜通透性之间的关系。通过固相合成线性前体和随后的溶液相大内酰胺反应制备了PF1171F类似物。核磁共振谱和分子模拟分析表明，PF1171F在不同溶剂中的主要三维构象与其X射线晶体结构相似。这种构象的类似物往往对家蚕表现出强烈的麻痹作用，表明该构象在麻痹中的意义。生物活性依赖于给药方式，在血淋巴注射和口服给药之间有所不同。类似物的平行人工膜通透性分析(PAMPA)显示，通过血淋巴注射，膜通透性与麻痹活性之间存在相关性，表明PF1171F的靶分子存在于细胞膜内。
PF1171 hexapeptides, a family of cyclic hexapeptides produced by fungi, exhibit paralyzing effects on the larvae of silkworms via oral administration. To elucidate the structural features of PF1171 hexapeptides that are crucial for bioactivity, the relationship among 3D structure, bioactivity, and membrane permeability of PF1171F (the peptide with the highest bioavailability) was systematically analyzed through the synthesis of 22 analogues. The PF1171F analogues were prepared by the solid-phase synthesis of a linear precursor and subsequent solution-phase macrolactamization. Analysis by NMR spectroscopy and molecular modeling indicated that the major 3D conformations of PF1171F in various solvents resemble its X-ray crystal structure. The analogues with this conformation tend to exhibit potent paralysis against silkworms, indicating the significance of the conformation in the paralysis. The biological activity was dependent on the mode of administration, varying between hemolymph injection and oral administration. Parallel artificial membrane permeability assay (PAMPA) of the analogues revealed a correlation between membrane permeabilities and paralytic activity by hemolymph injection, indicating that the target molecule of PF1171F is present inside the cell membrane.