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首页> 外文期刊>The Journal of Antibiotics: An International Journal >The Potent Immunosuppressive Cyclosporin FR901459 Inhibits the Human P-Glycoprotein and Formyl Peptide Receptor Functions
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The Potent Immunosuppressive Cyclosporin FR901459 Inhibits the Human P-Glycoprotein and Formyl Peptide Receptor Functions

机译：强大的免疫抑制环孢菌素FR901459抑制人类P-糖蛋白和甲酰肽受体功能

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By sequestering cytosolic calcineurin into a molecular complex with cyclophilin and its consequent T-cell dysfunction, some cyclosporins, such as CsA and FR901459 ([Thr~2-Leu~5-Leu~(10)]-CsA), display potent immunosuppressive activity. Independently on this property, cyclosporins may display one or more other biological activities mediated by interaction with cell surface glycoproteins. Several cyclosporins inhibit the function of human MDR1-encoded P-glycoprotein(Pgp), a flippase known to cause cancer multidrug resistance,but also expressed by some normal immunocompetent cells and by normal epithelial cells which control drug bioavailability in vivo. CsA is known to be a ptent Pgp inhibitor with a 3.2#mu#M IC_(50)in an assay where the most potent derivative SDZ PSC 833 gives a 0.49 #mu#M IC_(50). FR901459 is now shown to be a good Pgp inhibitor, being 2-fold weaker only (IC_(50) of 6#mu#M) than CsA. Some cyclosporins may also inhibit the function of the human FPR1-encoded formayl peptide receptor (FPR),a chemotactic receptor whose absence is known to impair antibacterial immunity. Yet this inhibition is very weak for all, but one of them, CsH, whose 0.15 #mu#M IC_(50) makes it a much more potent FPR inhibitor than CsA (IC_(50)>10 #mu#M in the same assay). FR901459 is now shown to be a very potent inhibitor of FPR function (IC_(50) of 0.6 #mu#M). Since CsH shows little Pgpinhibitory activity and has no known immunosuppressive activity, FR901459 displays a unique pharmacological profile:like CsA, it inhibits T-cell function;less than CsA, it can inhibit Pgp function on selected leukocyte subsets and on epithelial barriers known to control frug bioavailability; however, much more efficiently than CsA, it can inhibit the FPR function, a receptor involved in some leukocytic inflammatory responses to chemotactic peptides.
机译：通过将胞质钙调神经磷酸酶与亲环素及其随后的T细胞功能障碍隔离为分子复合物，某些环孢菌素，例如CsA和FR901459（[Thr〜2-Leu〜5-Leu〜（10）]-CsA），显示出强大的免疫抑制活性。独立于此性质，环孢菌素可表现出一种或多种其他与细胞表面糖蛋白相互作用介导的生物学活性。几种环孢菌素可抑制人类MDR1编码的P-糖蛋白（Pgp）的功能，Pgp是一种已知的引起癌症多药耐药的翻转酶，但也可由某些正常的免疫功能细胞和控制体内生物利用度的正常上皮细胞表达。在最有效的衍生物SDZ PSC 833给出0.49＃mu＃M IC_（50）的分析中，已知CsA是具有3.2＃mu＃M IC_（50）的Pgp抑制剂。现在显示FR901459是一种好的Pgp抑制剂，仅比CsA弱2倍（IC_（50）为6＃mu＃M）。一些环孢菌素也可能抑制人类FPR1编码的甲酰肽受体（FPR）的功能，该受体是一种趋化性受体，已知其缺乏会削弱抗菌素免疫力。然而，这种抑制作用对所有人都非常弱，但其中之一是CsH，其0.15＃mu＃M IC_（50）使它成为比CsA更有效的FPR抑制剂（在同一条件下，IC_（50）> 10＃mu＃M分析）。现在显示FR901459是非常有效的FPR功能抑制剂（IC_（50）为0.6＃mu＃M）。由于CsH几乎没有抑制Pgp的活性并且没有已知的免疫抑制活性，因此FR901459表现出独特的药理特性：像CsA一样，它抑制T细胞功能;与CsA相比，它可以抑制所选白细胞亚群和已知可控制的上皮屏障上的Pgp功能节食生物利用度;然而，它比CsA更有效地抑制FPR功能，FPR是一种参与趋化肽的白细胞炎症反应的受体。

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