Synthesis of lipid A and its analogues for investigation of the structural basis for their bioactivity
Synthesis of lipid A and its analogues for investigation of the structural basis for their bioactivity
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DOI：
10.1179/096805105x76841
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发表时间：
2005-12-01
期刊：
影响因子：
--
通讯作者：
Kusumoto, S
中科院分区：
文献类型：
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作者：
Fujimoto, Y;Adachi, Y;Kusumoto, S
为了阐明脂质a衍生物的内毒和拮抗活性的结构要求，我们在本研究中重点研究了1-和4'位置上的酰基部分和酸性基团的作用。我们合成了一种新的类似物，与大肠杆菌脂质a相比，该类似物在两个酰基较短的葡萄糖胺残基（癸烷基[c10]和十二烷基[c12]）上具有对称分布的特征，羧基甲基类似物的一个磷酸被羧基甲基取代，酰基分布不同。生物学试验表明，酰基的分布对其生物活性有很大影响。合成的Ru。明胶脂A型对LPS具有较强的拮抗活性，而其1- o -羧甲基类似物的内毒活性较弱。这些结果表明，当脂质A具有较短的（C-10, C-12）六酰基时，脂质A的生物活性容易受到微小结构差异的影响，如酸性基团的差异或酰基分布的差异，生物活性在该结构边界上由内毒素变为激动剂或反之亦然。基于分子力学计算，我们还设计并合成了具有酸性氨基酸残基的脂质A类似物，以取代非还原端磷酸化葡萄糖胺。根据脂质A类似物中酸性基团（磷酸或羧酸）的不同，还观察到内毒或拮抗活性的明确转换。
As a step to elucidate the structural requirements for the endotoxic and antagonistic activity of lipid A derivatives, we have focused, in the present study, on the effects of the acyl moieties and acidic groups at the 1- and 4'-positions. We synthesized a new analogue corresponding to Rubrivivax gelatinosus lipid A, which has a characteristic symmetrical distribution of acyl groups on the two glucosamine residues with shorter acyl groups ( decanoyl groups [ C 10] and lauryl groups [ C 12]) than Escherichia coli lipid A. Carboxymethyl analogues in which one of the phosphates was replaced with a carboxymethyl group were also synthesized with different distribution of acyl groups. Biological tests revealed that the distribution of acyl groups strongly affected the bioactivity. The synthetic Ru. gelatinosus type lipid A showed potent antagonistic activity against LPS, whereas its 1-O-carboxymethyl analogue showed weak endotoxic activity. These results demonstrated that when the lipid A has shorter (C-10, C-12) hexa-acyl groups, the bioactivity of lipid A is easily affected with small structural difference, such as the difference of acidic group or the distribution of acyl groups, and the bioactivity changes from endotoxic to agonistic or vice versa at this structural boundary for the bioactivity. We also designed, based on molecular mechanics calculations, and synthesized lipid A analogues possessing acidic amino acid residues in place of the non-reducing end phosphorylated glucosamine. Definite switching of the endotoxic or antagonistic activity was also observed depending on the difference of the acidic groups ( phosphoric acid or carboxylic acid) in the lipid A analogues.