Tiberghien F, Wenandy T, Loor F
Immunology Laboratory, Biotechnology and Pharmacology Research Center, Strasbourg 1 University, Illkirch, France.
J Antibiot (Tokyo). 2000 May;53(5):509-15. doi: 10.7164/antibiotics.53.509.
By sequestering cytosolic calcineurin into a molecular complex with cyclophilin and its consequent T-cell dysfunction, some cyclosporins, such as CsA and FR901459 ([Thr2-Leu5-Leu10]-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 MDRI-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 potent Pgp inhibitor with a 3.2 microM IC50 in an assay where the most potent derivative SDZ PSC 833 gives a 0.49 microM IC50. FR901459 is now shown to be a good Pgp inhibitor, being 2-fold weaker only (IC50 of 6 microM) than CsA. Some cyclosporins may also inhibit the function of the human FPR1-encoded formyl 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 micro/M IC50 makes it a much more potent FPR inhibitor than CsA (IC50 >10 microM in the same assay). FR901459 is now shown to be a very potent inhibitor of FPR function (IC50 of 0.6 microM). Since CsH shows little Pgp-inhibitory 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 drug bioavailability; however, much more efficiently than CsA, it can inhibit the FPR function, a receptor involved in some leukocytic inflammatory responses to chemotactic peptides.
通过将细胞质中的钙调磷酸酶隔离到与亲环蛋白形成的分子复合物中，进而导致T细胞功能障碍，一些环孢菌素，如环孢素A（CsA）和FR901459（[苏氨酸2-亮氨酸5-亮氨酸10]-CsA），表现出强大的免疫抑制活性。独立于这一特性，环孢菌素可能表现出一种或多种由与细胞表面糖蛋白相互作用介导的其他生物学活性。几种环孢菌素可抑制人类多药耐药蛋白1（MDRI）编码的P-糖蛋白（Pgp）的功能，Pgp是一种已知会导致癌症多药耐药的翻转酶，但也由一些正常的免疫活性细胞和控制体内药物生物利用度的正常上皮细胞表达。已知CsA是一种有效的Pgp抑制剂，在一项检测中其IC50为3.2微摩尔，而最有效的衍生物SDZ PSC 833的IC50为0.49微摩尔。现已证明FR901459是一种良好的Pgp抑制剂，其效力仅比CsA弱2倍（IC50为6微摩尔）。一些环孢菌素还可能抑制人类甲酰肽受体1（FPR1）编码的甲酰肽受体（FPR）的功能，FPR是一种趋化受体，已知其缺失会损害抗菌免疫。然而，除了CsH之外，其他所有环孢菌素对FPR的抑制作用都非常弱，CsH的IC50为0.15微摩尔/升，使其成为比CsA（在同一检测中IC50>10微摩尔）更强效的FPR抑制剂。现已证明FR901459是FPR功能的非常有效的抑制剂（IC50为0.6微摩尔）。由于CsH几乎没有Pgp抑制活性且没有已知的免疫抑制活性，FR901459表现出独特的药理学特征：与CsA一样，它抑制T细胞功能；比CsA弱，它可以抑制选定白细胞亚群和已知控制药物生物利用度的上皮屏障上的Pgp功能；然而，比CsA更有效得多的是，它可以抑制FPR功能，FPR是一种参与某些白细胞对趋化肽的炎症反应的受体。
