Synthesis and proinflammatory properties of muramyl tripeptides containing lysine and diaminopimelic acid moieties
Synthesis and proinflammatory properties of muramyl tripeptides containing lysine and diaminopimelic acid moieties
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DOI：
10.1002/cbic.200500181
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发表时间：
2005-11-01
期刊：
影响因子：
3.2
通讯作者：
Boons, GJ
中科院分区：
文献类型：
--
作者：
Roychowdhury, A;Wolfert, MA;Boons, GJ
通过适当保护的乙烯基甘氨酸和烯丙基甘氨酸衍生物的交叉歧化反应制备了一种特殊的氨基酸--二氨基甲酸(DAP)。交叉偶联产物的催化氢化导致了双键的还原和保护基团的去除。得到的化合物被适当地保护，用于聚合物支撑的和溶液相合成的胞壁酰三肽2和3，这两个不同于异谷氨酰胺和DAP部分的a-羧酸的酰胺化。含DAP的胞壁酰二肽(1，MDP)、含DAP的胞壁酰三肽3、含赖氨酸的胞壁酰三肽4和5可诱导人单核细胞系表达肿瘤坏死因子-α，而不产生肿瘤坏死因子-α蛋白。观察到的翻译障碍可以通过与内毒素共同孵育来消除，从而产生明显的协同效应。化合物2不诱导肿瘤坏死因子-α基因的表达，也不与脂多糖有协同作用，这表明异谷氨酰胺和DAP部分的α-羧酸的酰胺化导致生物活性的丧失。有人提出，a-羧酸的酰胺化是病原体用来避免被天然免疫系统检测到的一种策略。此外，模式识别受体Nod1和NOD2可能参与了多肽与内毒素协同作用的诱导。
The unusual amino acid diaminopimelic acid (DAP) was prepared by cross metathesis of appropriately protected vinyl glycine and allyl glycine derivatives. Catalytic hydrogenation of the cross-coupling product resulted in reduction of the double bond and the removal of protecting groups. The resulting compounds were appropriately protected for the polymer-supported and solution-phase synthesis of muramyl tripeptides 2 and 3, which differ in the amidation of the a-carboxylic acids of the isoglutamine and DAP moieties. Muramyl dipeptide (1, MDP), the DAP-containing muramyl tripeptide 3, and the lysine-containing muramyl tripeptides 4 and 5 induced TNF-alpha gene expression without TNF-a protein production in a human monocytic cell line. The observed block in translation could be removed by co-incubation with LPS, resulting in an apparent synergistic effect. Compound 2 did not induce TNF-alpha gene expression, neither did it exhibit a synergistic effect with LPS; this indicates that amidation of the a-carboxylic acids of the isoglutamine and DAP moieties results in a loss of biological activity. It is proposed that amidation of a-carboxylic acids is a strategy that may be used by pathogens to avoid detection by the innate immune system. Furthermore, the pattern recognition receptors Nod1 and Nod2 have been implicated in the possible induction of a synergistic effect of muropeptides with LPS.