Pentamidine is an antiparasitic and apoptotic drug that selectively modifies ubiquitin
Pentamidine is an antiparasitic and apoptotic drug that selectively modifies ubiquitin
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DOI：
10.1002/cbdv.200590111
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发表时间：
2005-01-01
影响因子：
2.9
通讯作者：
Pérez, JM
中科院分区：
文献类型：
--
作者：
Nguewa, PA;Fuertes, MA;Pérez, JM
我们已经确定了羟乙基磺酸喷他脒 (2) 对原生动物寄生虫婴儿利什曼原虫前鞭毛体的细胞毒性特性。孵育 72 It 后，2 的杀利什曼活性比顺铂高 60 倍 (4)。喷他脒盐 2 比顺铂诱导更多的程序性细胞死亡 (PCD)，这与 DNA 合成的抑制和 G2/M 期细胞周期停滞有关。圆二色性 (CD) 数据表明 2 与小牛胸腺 DNA (CT-DNA) 的结合会诱导 DNA 双螺旋的构象变化，与 B -> A 转变一致。此外，CD 光谱观察到，2 与泛素的相互作用导致蛋白质 P-折叠层含量增加 6%。荧光光谱研究与 CD 数据一致，表明 2 的喷他脒部分会导致位于分子 β 簇上的 Ub 残基 Phe(4) 和 Phe(45) 的荧光显着降低，但不会导致 α 簇上的 Tyr(59) 的荧光显着降低。这些数据表明喷他脒特异性修饰β簇，即泛素的“基本面”。我们的结果表明喷他脒的生化作用机制可能是其与 DNA 和蛋白质双重结合的结果。
We have determined the cytotoxic properties of pentamidine isethionate (2) towards the promastigotes of the protozoan parasite Leishmania infantum. The leishmanicidal activity of 2 was 60 times higher after 72 It of incubation than that of cisplatin (4). The pentamidine salt 2 induced a higher amount of programmed cell death (PCD) than cisplatin, which is associated with inhibition of DNA synthesis and cell-cycle arrest in the G2/M phase. Circular dichroism (CD) data indicate that binding of 2 to calf-thymus DNA (CT-DNA) induces conformational changes in the DNA double helix, consistent with a B -> A transition. Moreover, the interaction of 2 with ubiquitin led to a 6% increase in the P-sheet content of the protein as observed by CD spectroscopy. Fluorescence-spectroscopy studies agreed with the CD data, showing that the pentamidine portion of 2 induces a significant decrease in the fluorescence of the Ub residues Phe(4) and Phe(45) located on the beta-cluster of the molecule, but not of Tyr(59) on the alpha-cluster. These data indicate that pentamidine specifically modifies the beta-cluster, i.e., the 'basic face' of ubiquitin. Our results suggest that the biochemical mechanism of action of pentamidine may be a consequence of its dual binding to DNA and proteins.