A Calcineurin-Independent Mechanism of Angiogenesis Inhibition by a Nonimmunosuppressive Cyclosporin A Analog
A Calcineurin-Independent Mechanism of Angiogenesis Inhibition by a Nonimmunosuppressive Cyclosporin A Analog
复制标题
DOI：
10.1124/jpet.111.180851
复制
发表时间：
2011-08-01
影响因子：
3.5
通讯作者：
Liu, Jun O.
中科院分区：
文献类型：
--
作者：
Nacev, Benjamin A.;Low, Woon-Kai;Liu, Jun O.
环孢素A （Cyclosporin A, CsA）是一种应用广泛的免疫抑制剂。它的免疫抑制作用是通过与亲环蛋白a （CypA）形成三元络合物来抑制蛋白磷酸酶钙调磷酸酶（calcalineurin）。CsA还能抑制内皮细胞增殖和血管生成。这也被认为是通过钙调神经磷酸酶抑制而发生的。然而，CsA也是亲环蛋白（一类脯氨酸异构酶）的有效抑制剂。由于钙调磷酸酶抑制需要结合，因此需要抑制CypA，钙调磷酸酶和亲环蛋白抑制在抗血管生成中的相对作用尚未得到解决。我们已经采取了化学生物学的方法，通过解离CsA的两种活性在分子水平上探索这个问题。我们已经确定了一种CsA的非免疫抑制类似物，它不抑制钙调神经磷酸酶，但保持对内皮细胞增殖和体内血管生成的抑制。同样的类似物也能抑制所有测试的亲环蛋白异构体。我们还表明，第二种结构独特的亲环蛋白抑制剂足以阻止内皮细胞增殖。这些结果表明，抑制亲环蛋白对CsA抗血管生成活性的作用可能比先前认为的更大，并且亲环蛋白可能是潜在的抗血管生成药物靶点。
Cyclosporin A (CsA) is a widely used immunosuppressant drug. Its immunosuppressive activity occurs through the inhibition of the protein phosphatase calcineurin via formation of a ternary complex with cyclophilin A (CypA). CsA also inhibits endothelial cell proliferation and angiogenesis. This has been thought to occur through calcineurin inhibition as well. However, CsA is also a potent inhibitor of cyclophilins, a class of prolyl isomerases. Because calcineurin inhibition requires binding, and therefore inhibition of CypA, the relative contributions of calcineurin and cyclophilin inhibition in antiangiogenesis have not been addressed. We have taken a chemical biology approach to explore this question by dissociating the two activities of CsA at the molecular level. We have identified a nonimmunosuppressive analog of CsA that does not inhibit calcineurin but maintains inhibition of endothelial cell proliferation and in vivo angiogenesis. The same analog also maintains inhibition of all cyclophilin isoforms tested. We also show that a second, structurally distinct, cyclophilin inhibitor is sufficient to block endothelial cell proliferation. These results suggest that the inhibition of cyclophilins may play a larger role in the antiangiogenic activity of CsA than previously believed, and that cyclophilins may be potential antiangiogenic drug targets.