Kusumoto Shoichi, Fukase Koichi, Fukase Yoshiyuki, Kataoka Mikayo, Yoshizaki Hiroaki, Sato Kenjiro, Oikawa Masato, Suda Yasuo
Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan.
J Endotoxin Res. 2003;9(6):361-6. doi: 10.1179/096805103225002737.
Our early work using homogeneous synthetic preparations demonstrated the presence of a lipid A analog which antagonizes endotoxic activities of LPS and lipid A. The first example was a tetraacylated biosynthetic precursor, now known as precursor Ia or lipid IVa, that contains four 3-hydroxytetradecanoyl moieties linked to the bisphosphorylated disaccharide backbone common to the endotoxic hexa-acyl Escherichia coli lipid A. Various compounds with both endotoxic and antagonistic activities have subsequently been reported from either natural or synthetic sources, but little is known about the factors determining the type of the activities of the respective compounds. To approach this issue, we have synthesized a series of lipid A analogs with various numbers and chain lengths of acyl groups on the backbone. Some were prepared by the aid of a novel affinity separation procedure. The phosphate moieties were also synthetically replaced. Biological tests showed that at least three acyl groups are required for antagonistic activity but one or even both of the phosphates can be replaced with other acidic moieties without losing the activity. The effect of Kdo residues linked to lipid A is also briefly discussed. Molecular dynamics calculations reasonably explain possible conformations required for the biological activity.
我们早期使用均相合成制剂的研究表明，存在一种脂质A类似物，它能拮抗脂多糖（LPS）和脂质A的内毒素活性。第一个例子是一种四酰化生物合成前体，现在被称为前体Ia或脂质IVa，它含有四个3-羟基十四烷酰基部分，与内毒素六酰基大肠杆菌脂质A共有的双磷酸化二糖主链相连。随后，从天然或合成来源报道了各种具有内毒素和拮抗活性的化合物，但对于决定各化合物活性类型的因素知之甚少。为了解决这个问题，我们合成了一系列在主链上具有不同数量和链长酰基的脂质A类似物。其中一些是借助一种新型亲和分离程序制备的。磷酸部分也进行了合成替换。生物学测试表明，拮抗活性至少需要三个酰基，但一个甚至两个磷酸可以被其他酸性部分取代而不丧失活性。还简要讨论了与脂质A相连的Kdo残基的作用。分子动力学计算合理地解释了生物活性所需的可能构象。
