Structural and Functional Analyses of the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir (S/GSK1349572)
Structural and Functional Analyses of the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir (S/GSK1349572)
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DOI：
10.1124/mol.111.073189
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发表时间：
2011-10-01
影响因子：
3.6
通讯作者：
Cherepanov, Peter
中科院分区：
文献类型：
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作者：
Hare, Stephen;Smith, Steven J.;Cherepanov, Peter
Raltegravir (RAL) 和相关的 HIV-1 整合酶 (IN) 链转移抑制剂 (INSTI) 可有效阻断体外病毒复制并抑制患者的病毒血症。这些小分子与 IN 活性位点结合，使其与病毒 DNA 3' 端的脱氧腺苷脱离。对 RAL 高度耐药的病毒株的出现凸显了开发具有改善耐药性的 INSTI 的迫切需要。在此，我们证明候选第二代药物多替拉韦（DTG，S/GSK1349572）可有效抑制一组对第一代 INSTI 耐药的 HIV-1 IN 变异体。为了阐明 DTG 对抗 RAL 抗性 IN 的效力增强的结构基础，我们确定了与该化合物结合的野生型和突变型原型泡沫病毒嵌体的晶体结构。 DTG 的整体 IN 结合模式与三环羟基吡咯 MK-2048 惊人地相似。两种第二代 INSTI 在 IN 活性位点内占据几乎相同的物理空间，并与催化核心结构域的 β 4-α 2 环接触。与 RAL 和其他 INSTI 制成的连接器区域相比，连接金属螯合核心和 DTG 卤代苄基的扩展接头区域使其能够更深入地进入被置换的病毒 DNA 碱基腾出的口袋，并与病毒 DNA 进行更密切的接触。此外，我们的结构表明，DTG 能够巧妙地重新调整其位置和构象，以响应 RAL 抗性 IN 活性位点的结构变化。
Raltegravir (RAL) and related HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) efficiently block viral replication in vitro and suppress viremia in patients. These small molecules bind to the IN active site, causing it to disengage from the deoxyadenosine at the 3' end of viral DNA. The emergence of viral strains that are highly resistant to RAL underscores the pressing need to develop INSTIs with improved resistance profiles. Herein, we show that the candidate second-generation drug dolutegravir (DTG, S/GSK1349572) effectively inhibits a panel of HIV-1 IN variants resistant to first-generation INSTIs. To elucidate the structural basis for the increased potency of DTG against RAL-resistant INs, we determined crystal structures of wild-type and mutant prototype foamy virus intasomes bound to this compound. The overall IN binding mode of DTG is strikingly similar to that of the tricyclic hydroxypyrrole MK-2048. Both second-generation INSTIs occupy almost the same physical space within the IN active site and make contacts with the beta 4-alpha 2 loop of the catalytic core domain. The extended linker region connecting the metal chelating core and the halobenzyl group of DTG allows it to enter farther into the pocket vacated by the displaced viral DNA base and to make more intimate contacts with viral DNA, compared with those made by RAL and other INSTIs. In addition, our structures suggest that DTG has the ability to subtly readjust its position and conformation in response to structural changes in the active sites of RAL-resistant INs.