Mechanism of action of the HIV-1 integrase inhibitory peptide LEDGF 361-370
Mechanism of action of the HIV-1 integrase inhibitory peptide LEDGF 361-370
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DOI：
10.1016/j.bbrc.2010.02.100
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发表时间：
2010-04-02
影响因子：
3.1
通讯作者：
Friedler, Assaf
中科院分区：
文献类型：
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作者：
Hayouka, Zvi;Levin, Aviad;Friedler, Assaf
HIV-1整合酶蛋白(IN)介导病毒基因与宿主基因组的整合，是抗HIV药物的靶点。我们最近描述了一种来自IN细胞伙伴蛋白LEDGF/p75残基361-370的多肽，它在体外抑制IN的催化活性和细胞内的HIV-1复制。在这里，我们对LEDGF 361-370在体外、细胞和体内的作用机制进行了全面的研究。丙氨酸扫描、荧光各向异性结合研究、同源模拟和核磁共振研究表明，LEDGF 361-370中的所有残基都有助于IN的结合和抑制。细胞动力学研究表明，LEDGF 361-370特异性地抑制病毒DNA的整合。因此，选择全肽进行体内研究，在小鼠模型中抑制HIV-1RNA的产生。我们的结论是，完整的LEDGF 361-370肽是一种有效的HIV-1抑制剂，可以作为抗HIV的先导化合物进一步开发。(C)2010 Elsevier Inc.保留所有权利。
The HIV-1 integrase protein (IN) mediates integration of the viral cDNA into the host genome and is a target for anti-HIV drugs. We have recently described a peptide derived from residues 361-370 of the IN cellular partner protein LEDGF/p75, which inhibited IN catalytic activity in vitro and HIV-1 replication in cells. Here we performed a comprehensive study of the LEDGF 361-370 mechanism of action in vitro, in cells and in vivo. Alanine scan, fluorescence anisotropy binding studies, homology modeling and NMR studies demonstrated that all residues in LEDGF 361-370 contribute to IN binding and inhibition. Kinetic studies in cells showed that LEDGF 361-370 specifically inhibited integration of viral cDNA. Thus, the full peptide was chosen for in vivo studies, in which it inhibited the production of HIV-1 RNA in mouse model. We conclude that the full LEDGF 361-370 peptide is a potent HIV-1 inhibitor and may be used for further development as an anti-HIV lead compound. (C) 2010 Elsevier Inc. All rights reserved.