2-Hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs), Novel Inhibitors of HIV Integrase with a High Barrier to Resistance
2-Hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs), Novel Inhibitors of HIV Integrase with a High Barrier to Resistance
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DOI：
10.1021/cb4000426
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发表时间：
2013-06-01
影响因子：
4
通讯作者：
Christ, Frauke
中科院分区：
文献类型：
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作者：
Desimmie, Belete A.;Demeulemeester, Jonas;Christ, Frauke
临床HIV-1整合酶（IN）链转移抑制剂（iniss）能有效抑制病毒复制，显著降低病毒载量。然而，对这些药物的耐药性的出现强调了开发具有改善耐药谱的下一代IN催化位点抑制剂的必要性。在这里，我们提出了一种新的候选IN抑制剂MB-76，一种2-羟基异喹啉-1,3(2H,4H)-二酮（HID）衍生物。MB-76有效地阻断HIV整合，并对一组野生型和抗替地韦的HIV-1变体有效。在细胞培养中缺乏与其他inis的交叉抗性和抗性选择，表明HID衍生物的整体结合模式与inis相似。其紧凑的支架显示了来自单个环的所有三个Mg2+螯合氧原子，确保与IN直接接触的只有PFV IN的不变P214和Q215残基（分别为HIV-1 IN的P145和Q146），这可能部分解释了选择复制抗性变体的困难。此外，连接MB-76金属螯合核心和对氟苯基的延伸的多重力连接体可以在抗重力蛋白的扰动活性位点提供额外的灵活性。所鉴定的化合物代表了作为下一代HIV IN催化位点抑制剂进一步（预）临床开发的潜在候选物。
Clinical HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) potently inhibit viral replication with a dramatic drop in viral load. However, the emergence of resistance to these drugs underscores the need to develop next-generation IN catalytic site inhibitors with improved resistance profiles. Here, we present a novel candidate IN inhibitor, MB-76, a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) derivative. MB-76 potently blocks HIV integration and is active against a panel of wild type as well as raltegravir-resistant HIV-1 variants. The lack of cross-resistance with other INSTIs and the absence of resistance selection in cell culture indicate the potential of HID derivatives overall binding mode similar to that of INSTIs. Its compact scaffold displays all three Mg2+ chelating oxygen atoms from a single ring, ensuring that the only direct contacts with IN are the invariant P214 and Q215 residues of PFV IN (P145 and Q146 for HIV-1 IN, respectively), which may partially explain the difficulty of selecting replicating resistant variants. Moreover, the extended, dolutegravir-like linker connecting the MB-76 metal chelating core and p-fluorobenzyl group can provide additional flexibility in the perturbed active sites of raltegravir-resistant INs. The compound identified represents a potential candidate for further (pre)clinical development as next-generation HIV IN catalytic site inhibitor.