Convergent Synthesis of Novel Muramyl Dipeptide Analogues: Inhibition of Porphyromonas gingivalis-Induced Pro-inflammatory Effects by High Doses of Muramyl Dipeptide
Convergent Synthesis of Novel Muramyl Dipeptide Analogues: Inhibition of Porphyromonas gingivalis-Induced Pro-inflammatory Effects by High Doses of Muramyl Dipeptide
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DOI：
10.1021/acs.jmedchem.6b00681
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发表时间：
2016-07-28
影响因子：
7.3
通讯作者：
Amar, Salomon
中科院分区：
文献类型：
--
作者：
Cai, Bin;Panek, James S.;Amar, Salomon
牙龈卟啉单胞菌（P.g.）-胞壁酰二肽（MDP）可以以双相浓度依赖性方式影响诱导的TNF-α。我们发现在P.G.-暴露的巨噬细胞，用10 μ g/mL的MDP（MDP-低）处理使TNF-α上调29%，而100 μ g/mL或更高（MDP-高）显著降低TNF-α（16%至38%）。发现MDP-high影响泛素编辑酶A20和激活蛋白1（AP 1）。在A20的启动子区发现了AP 1结合位点。A20启动子活性在AP 1 cDNA转染细胞后上调。通过使用肽偶联试剂EDCI和HOAt合成两个独特的碳水化合物片段7a和7 b的收敛策略制备MDP的四种类似物（3-6）。表4改善了MDP功能和P.g.-诱导活动。我们提出了一个新的信号通路TNF-α诱导激活后，暴露于巨噬细胞P.g.和MDP-high或类似物4。
Porphyromonas gingivalis (P.g.)-induced TNF-alpha can be affected by muramyl dipeptide (MDP) in a biphasic concentration-dependent manner. We found that in P.g.-exposed macrophages, treatment with 10 mu g/mL of MDP (MDP-low) up-regulated TNF-alpha by 29%, while 100 mu g/mL or higher (MDP-high) significantly decreased it (16% to 38%). MDP-high was found to affect the ubiquitin-editing enzyme A20 and activator protein 1 (AP1). An AP1 binding site was found in the promoter region of A20. A20 promoter activity was up-regulated after transfection of AP1 cDNA in cells. Four analogues of MDP (3-6) were prepared through a convergent strategy involving the synthesis of two unique carbohydrate fragments, 7a and 7b, using the peptide coupling reagents, EDCI and HOAt. Analogue 4 improved MDP function and P.g.-induced activities. We propose a new signaling pathway for TNF-alpha induction activated after exposing macrophages to both P.g. and MDP-high or analogue 4.