Synthesis and Toll-like Receptor 4 (TLR4) Activity of Phosphatidylinositol Dimannoside Analogues

被引:16
作者
Ainge, Gary D. [2 ,3 ]
Martin, William John [1 ]
Compton, Benjamin J. [2 ]
Hayman, Colin M. [2 ]
Larsen, David S. [3 ]
Yoon, Sung-il [4 ]
Wilson, Ian A. [4 ]
Harper, Jacquie L. [1 ,5 ]
Painter, Gavin F. [2 ]
机构
[1] Malaghan Inst Med Res, Wellington, New Zealand
[2] Ind Res Ltd, Carbohydrate Chem Team, Lower Hutt, New Zealand
[3] Univ Otago, Dept Chem, Dunedin, New Zealand
[4] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA
[5] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA
关键词
BACILLUS-CALMETTE-GUERIN; ENANTIOMERICALLY PURE; CHEMICAL-SYNTHESIS; MANNOSIDES; EFFICIENT; AGONISTS; ANTIGEN; GLYCOSYLATION; MACROPHAGES; SUPPRESSION;
D O I
10.1021/jm2008419
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of five PIM2 analogues were synthesized and tested for their ability to activate primary macrophages and modulate LPS signaling. Structural changes included replacement of the fatty acid esters of the phosphatidyl moiety of PIM2 with the corresponding ether or amide. An AcPIM2 analogue possessing an ether linkage was also prepared. The synthetic methodology utilized an orthogonally protected chiral myo-inositol starting material that was conveniently prepared from myo-inositol in just two steps. Important steps in the synthetic protocols included the regio- and alpha-selective glycosylation of inositol O-6 and introduction of the phosphodiester utilizing phosphoramidite chemistry. Replacement of the inositol core with a glycerol moiety gave compounds described as phosphatidylglycerol dimannosides (PGM(2)). Biological testing of these PIM compounds indicated that the agonist activity was TLR4 dependent. An ether linkage increased agonist activity. Removal of the inositol ring enhanced antagonist activity, and the presence of an additional lipid chain enhanced LPS-induced cytokine production in primary macrophages. Furthermore, the interruption of the LPS-induced 2:2 TLR4/MD-2 signaling complex formation by PIM2 represents a previously unidentified mechanism involved in the bioactivity of PIM molecules.
引用
收藏
页码:7268 / 7279
页数:12
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