Rational design and synthesis of novel dimeric diketoacid-containing inhibitors of HIV-1 integrase: Implication for binding to two metal ions on the active site of integrase
Rational design and synthesis of novel dimeric diketoacid-containing inhibitors of HIV-1 integrase: Implication for binding to two metal ions on the active site of integrase
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DOI：
10.1021/jm030559k
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发表时间：
2004-05-06
影响因子：
7.3
通讯作者：
Neamati, N
中科院分区：
文献类型：
--
作者：
Long, YQ;Jiang, XH;Neamati, N
含二酮酸类化合物作为HIV-1整合酶(IN)抑制剂的发现在验证该酶作为抗HIV感染治疗药物的重要靶点方面发挥了重要作用。事实上，第一个临床使用的含有三唑环作为羧酸部分的生物同工酶的IN抑制剂S-1360就属于这类化合物。了解二价金属络合在抑制IN中的作用(J.Med.化学。2002年，45,56615670)，我们设计并合成了一系列新型的二聚体二酮类化合物，这些二聚体化合物可以同时与IN活性中心上的两个二价金属离子结合。我们合理地认为，由独特设计的连接子分开的两个diketo亚基可以潜在地螯合两个金属离子，这两个金属离子要么来自一个IN活性中心，要么来自两个并列在高阶四聚体中的活性中心。在这里，我们表明所有的新化合物都对纯化的IN具有不同的链转移选择性，并且一些类似物在感染的CEM细胞中对HIV-1的细胞病变作用具有很强的抑制作用。本研究首次尝试将两种二价金属离子合理地定位于IN的活性部位，并可能对第二代含二酮酸类抑制剂的设计具有潜在的指导意义。
Discovery of diketoacid-containing compounds as HIV-1 integrase (IN) inhibitors played a major role in validating this enzyme as an important target for the development of therapeutics against HIV infection. In fact, S-1360, the first clinically used IN inhibitor containing a triazole ring as a bioisostere of a carboxylic acid moiety belongs to this class of compounds. To understand the role of divalent metal-chelating in the inhibition of IN (J. Med. Chem. 2002, 45, 56615670), we designed and synthesized a series of novel dimeric diketo-containing compounds with the notion that such dimeric compounds may simultaneously bind to two divalent metal ions on the active site of IN. We rationalized that the two diketo subunits separated by uniquely designed linkers can potentially chelate two metal ions that are either provided from one IN active site or two active sites juxtaposed together in a higher order tetramer. Herein, we show that all the new compounds are highly potent against purified IN with varied selectivity for strand transfer, and that some of the analogues exert potent inhibition of the cytopathic effect of HIV-1 in infected CEM cells. This study represents the first attempt to rationally target two divalent metal ions on the active site of IN and may have potential implications for the design of second generation diketoacid-containing class of inhibitors.