Isolation and Structures of Novel Fungal Metabolites as Chemokine Receptor(CCR2)Antagonists

Kithsiri B.Herath; Hiranthi Jayasuriya; John G.Ondeyka; Jon D.Polishook; Gerald F.Bills

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Isolation and Structures of Novel Fungal Metabolites as Chemokine Receptor(CCR2)Antagonists

机译：新型真菌代谢产物作为趋化因子受体（CCR2）拮抗剂的分离与结构

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The chemokine receptor,CCR2,is predominantly expressed on monocytes/macrophages,and on a subset of memory T cells.It binds to several CC type chemokines of the monocyte chemoattractant protein(MCP)family of which MCP-1 exhibits the highest affinity.CCR2/MCP-1 expression/association in monocyte/macro-phage/T cells has been associated with inflammatory processes such as rheumatoid arthritis,multiple sclerosis and atherosclerosis.Neutralization of CCR2 with either a peptide or receptor antagonist results in the prevention of joint swelling in rodent models of arthritis.In this paper,bioassay-guided discovery of CCR2 receptor antagonists derived from natural product extracts are reported.These antagonists belong to two main classes exemplified by bis-thiodiketopiperazines and cytochalasins.Six compounds,including emestrin,two new emestrin analogs,and chaetomin represent the first group of compounds.These compounds inhibited the binding of MCP-1 to CCR2(CHO membrane)with IC_(50)values of 0.8 to 9 muM and exhibited good activity in a whole cell assay using MCP-1 and human monocytes with IC_(50'S)ranging from 4-9 muM.Cytochalasins A and B represented the second group and inhibited the binding activity with IC_(50)values of 5 and 188 muM,respectively.This is the first report of natural product antagonists of the CCR2 receptor.

机译：趋化因子受体CCR2主要在单核细胞/巨噬细胞和一部分记忆T细胞上表达，它与单核细胞趋化蛋白（MCP）家族的几个CC型趋化因子结合，其中MCP-1的亲和力最高。 / MCP-1在单核细胞/巨噬细胞/ T细胞中的表达/关联与类风湿性关节炎，多发性硬化和动脉粥样硬化等炎症过程有关.CCR2与肽或受体拮抗剂的中和作用可预防关节的肿胀本文报道了天然产物提取物中CCR2受体拮抗剂的生物测定指导发现，这些拮抗剂属于双硫代二酮哌嗪和细胞松弛素的两个主要类别。六种化合物，包括Emestrin，两种新的Emestrin类似物，并且chaetomin代表第一类化合物。这些化合物抑制了MCP-1与CCR2（CHO膜）的结合，IC_（50）值为0。 8至9μM，在使用MCP-1和人单核细胞的全细胞试验中表现出良好的活性，IC_（50'S）为4-9μM。细胞松弛素A和B代表第二组，并抑制与IC_（50）的结合活性CCR2受体的天然产物拮抗剂的首次报道分别为5和188μM。

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来源
《The Journal of Antibiotics: An International Journal》 |2005年第11期|共9页
作者
Kithsiri B.Herath; Hiranthi Jayasuriya; John G.Ondeyka; Jon D.Polishook; Gerald F.Bills;
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正文语种 eng
中图分类药学;
关键词
CCR2 antagonists; natural products; bis-thioketopiperazines; microbial products;

机译：CCR2拮抗剂;天然产物;双硫代酮哌嗪;微生物产物;

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1. Isolation and Structures of Novel Fungal Metabolites as Chemokine Receptor(CCR2)Antagonists [J] . Kithsiri B.Herath, Hiranthi Jayasuriya, John G.Ondeyka, The Journal of Antibiotics: An International Journal . 2005,第11期

机译：新型真菌代谢产物作为趋化因子受体（CCR2）拮抗剂的分离与结构
2. A Family of Depsi-peptide Fungal Metabolites, as Selective and Competitive Human Tachykinin Receptor (NK_2)Antagonists: Fermentation, Isolation, Physico-chemical Properties, and Biological Activity [J] . Vinod R.Hegde, Mohindar S.Puar, Ping Dai, The Journal of Antibiotics: An International Journal . 2001,第2期

机译：Depsi肽真菌代谢产物家族，作为选择性和竞争性人类速激肽受体（NK_2）拮抗剂：发酵，分离，物理化学性质和生物活性。
3. Family of depsi-peptide fungal metabolites, as selective and competitive human tachykinin receptor (NK2) antagonists: Fermentation, isolation, physico-chemical properties, and biological activity [J] . Hegde VR., Dai P., Pu H., The Journal of Antibiotics: An International Journal . 2001,第2期

机译：作为选择性和竞争性人速激肽受体（NK2）拮抗剂的depsi-肽真菌代谢物家族：发酵，分离，理化性质和生物学活性
4. Development of Chemokine Receptor CXCR4 Antagonists Using Bio-mimetic Strategy [C] . Hirokazu Tamamura, Tomohiro Tanaka, Hiroshi Tsutsumi American Peptide Symposium . 2009

机译：使用生物模拟策略的趋化因子受体CXCR4拮抗剂的发展
5. Prediction of structure and antagonist binding site in human and rodent chemokine receptor 1. [D] . Sharma, Shantanu. 2005

机译：人类和啮齿动物趋化因子受体1的结构和拮抗剂结合位点的预测
6. Effect of PF-04634817 an Oral CCR2/5 Chemokine Receptor Antagonist on Albuminuria in Adults with Overt Diabetic Nephropathy [O] . Jeremy D. Gale, Steven Gilbert, Samuel Blumenthal, 2018

机译：口服CCR2 / 5趋化因子受体拮抗剂PF-04634817对糖尿病性肾病成人蛋白尿的影响
7. The simultaneous blockade of chemokine receptors CCR2, CCR5 and CXCR3 by a non-peptide chemokine receptor antagonist protects mice from dextran sodium sulfate-mediated colitis [O] . Hirotake Tokuyama, Satoshi Ueha, Makoto Kurachi, 2005

机译：非肽趋化因子受体拮抗剂的同时阻断趋化因子受体CCR2，CCR5和CXCR3保护小鼠免受葡聚糖硫酸钠介导的结肠炎
8. Development of Peptide Antagonists of Chemokine Receptors Involved in Breast Cancer Metastasis [R] . Blondelle, S. E. 2005

机译：趋化因子受体多肽拮抗剂参与乳腺癌转移的研究进展

Isolation and Structures of Novel Fungal Metabolites as Chemokine Receptor(CCR2)Antagonists

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