Identification of cellular deoxyhypusine synthase as a novel target for antiretroviral therapy
Identification of cellular deoxyhypusine synthase as a novel target for antiretroviral therapy
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DOI：
10.1172/jci200521949
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发表时间：
2005-01-01
影响因子：
15.9
通讯作者：
Hauber, J
中科院分区：
文献类型：
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作者：
Hauber, I;Bevec, D;Hauber, J
高效抗逆转录病毒疗法(HAART)的引入显著降低了HIV-1感染者的发病率和死亡率。然而，HIV-1对目前所有针对病毒逆转录酶、蛋白酶和gp4l的抗逆转录病毒药物都具有耐药性。此外，在越来越多的患者中，多药耐药病毒的发展损害了HAART的疗效，限制了治疗选择。因此，开发新药和确定抗逆转录病毒治疗的新靶点是一项持续的任务。在这里，我们确定鸟苷酮CNI-1493是一种有效的人脱氧亚硫氨酸合成酶(DHS)抑制剂。通过抑制DHS，该化合物抑制亚硫氨酸的形成，从而抑制真核细胞起始因子5A(eIF-SA)的激活，EIF-SA是HIV-I REV调节蛋白的细胞辅助因子。我们证明了CNI-1493或RNA干扰抑制DHS有效地抑制了细胞培养和原代细胞中的逆转录病毒复制周期。我们发现CNI-1493抑制巨噬细胞和T细胞嗜性的实验室菌株、临床分离株和对病毒蛋白酶和逆转录酶抑制剂具有高水平耐药性的病毒株的复制。此外，没有观察到可测量的药物对细胞周期转变、细胞凋亡和一般细胞毒性的不良影响。因此，人类DHS是开发先进的抗逆转录病毒疗法，特别是抑制多药耐药病毒的新的和有前途的药物靶点。
The introduction of highly active antiretroviral therapy (HAART) has significantly decreased morbidity and mortality among patients infected with HIV- 1. However, HIV- 1 can acquire resistance against all currently available antiretroviral drugs targeting viral reverse transcriptase, protease, and gp4l. Moreover, in a growing number of patients, the development of multidrug-resistant viruses compromises HAART efficacy and limits therapeutic options. Therefore, it is an ongoing task to develop new drugs and to identify new targets for antiretroviral therapy. Here, we identified the guanylhydrazone CNI-1493 as an efficient inhibitor of human deoxyhypusine synthase (DHS). By inhibiting DHS, this compound suppresses hypusine formation and, thereby, activation of eukaryotic initiation factor 5A (eIF-SA), a cellular cofactor of the HIV- I Rev regulatory protein. We demonstrate that inhibition of DHS by CNI- 1493 or RNA interference efficiently suppressed the retroviral replication cycle in cell culture and primary cells. We show that CNI-1493 inhibits replication of macrophage- and T cell-tropic laboratory strains, clinical isolates, and viral strains with high-level resistance to inhibitors of viral protease and reverse transcriptase. Moreover, no measurable drug-induced adverse effects on cell cycle transition, apoptosis, and general cytotoxicity were observed. Therefore, human DHS represents a novel and promising drug target for the development of advanced antiretroviral therapies, particularly for the inhibition of multidrug-resistant viruses.