Crystal Structures of Novel Allosteric Peptide Inhibitors of HIV Integrase Identify New Interactions at the LEDGF Binding Site
Crystal Structures of Novel Allosteric Peptide Inhibitors of HIV Integrase Identify New Interactions at the LEDGF Binding Site
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DOI：
10.1002/cbic.201100350
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发表时间：
2011-10-17
期刊：
影响因子：
3.2
通讯作者：
Deadman, John J.
中科院分区：
文献类型：
--
作者：
Rhodes, David I.;Peat, Thomas S.;Deadman, John J.
优化的溶液环化方法使我们能够获得一系列肽，包括 SLKIDNLD (2)。我们研究了 HIV 整合酶 (HIV-IN) 催化核心结构域与 13 个肽的晶体复合物，并鉴定了结合位点的多种相互作用，包括与残基 Thr125 和 Gln95 的氢键，这些相互作用此前未被描述为在结合位点内可接近。我们在邻近 AlphaScreen 测定和 LEDGF 增强 HIV-IN 链转移的测定中表明，这些肽可抑制晶状体上皮衍生生长因子 (LEDGF) 与 HIV-IN 的相互作用。所确定的相互作用代表了开发新型 HIV-IN 抑制剂的潜在框架。
An optimised method of solution cyclisation gave us access to a series of peptides including SLKIDNLD (2). We investigated the crystallographic complexes of the HIV integrase (HIV-IN) catalytic core domain with 13 of the peptides and identified multiple interactions at the binding site, including hydrogen bonds with residues Thr125 and Gln95, that have not previously been described as being accessible within the binding site. We show that the peptides inhibit the interaction of lens epithelium-derived growth factor (LEDGF) with HIV-IN in a proximity AlphaScreen assay and in an assay for the LEDGF enhancement of HIV-IN strand transfer. The interactions identified represent a potential framework for the development of new HIV-IN inhibitors.