Preferential inhibition of the magnesium-dependent strand transfer reaction of HIV-1 integrase by α-hydroxytropolones
Preferential inhibition of the magnesium-dependent strand transfer reaction of HIV-1 integrase by α-hydroxytropolones
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DOI：
10.1124/mol.105.020321
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发表时间：
2006-04-01
影响因子：
3.6
通讯作者：
Pommier, Y
中科院分区：
文献类型：
--
作者：
Semenova, EA;Johnson, AA;Pommier, Y
整合是人类免疫缺陷病毒1型（HIV-1）生命周期中的关键步骤;因此，HIV-1整合酶抑制剂是抗逆转录病毒治疗的候选药物。发现两种7-羟基托酚酮衍生物（α-羟基托酚酮）抑制HIV-1整合酶。对来自美国国家癌症研究所化合物库的几种托酚酮衍生物的构效关系研究表明，7-羟基对整合酶抑制是必不可少的。α-羟基环庚三烯酚酮优先抑制链转移，并且在镁或锰的存在下都是抑制性的。在镁存在下缺乏崩解抑制，加上来自不同交联测定的结果表明α-羟基环庚三烯酚酮为界面抑制剂。我们提出α-羟基环酚酮螯合酶活性位点中的二价金属（Mg 2+或Mn 2+）。在生物化学试验中对HIV-1整合酶最具活性的化合物[2，4，6-环庚三烯-1-酮，2，7-二羟基-4-异丙基（NSC 18806）IC 50 = 4.8 +/- 2.5 μ M]在基于细胞的试验中对HIV-1（IIIB）表现出较弱的细胞保护活性。α-羟基环庚三烯酚酮代表了一个新的抑制剂家族，用于开发抗HIV感染的新药。
Integration is a crucial step in the life cycle of human immunodeficiency virus type 1 (HIV-1); therefore, inhibitors of HIV-1 integrase are candidates for antiretroviral therapy. Two 7-hydroxytropolone derivatives (alpha-hydroxytropolones) were found to inhibit HIV-1 integrase. A structure-activity relationship investigation with several tropolone derivatives from The National Cancer Institute compound repository demonstrated that the 7-hydroxy group is essential for integrase inhibition. alpha-Hydroxytropolones preferentially inhibit strand transfer and are inhibitory both in the presence of magnesium or manganese. Lack of inhibition of disintegration in the presence of magnesium coupled with results from different cross-linking assays suggests alpha-hydroxytropolones as interfacial inhibitors. We propose that alpha-hydroxytropolones chelate the divalent metal (Mg2+ or Mn2+) in the enzyme active site. The most active compound against HIV-1 integrase in biochemical assays [ 2,4,6-cycloheptatrien-1-one, 2,7-dihydroxy-4-isopropyl (NSC 18806) IC50 = 4.8 +/- 2.5 mu M] exhibits weak cytoprotective activity against HIV-1(IIIB) in a cell-based assay. alpha-Hydroxytropolones represent a new family of inhibitors for the development of novel drugs against HIV infection.