Integrase Inhibitor Prodrugs: Approaches to Enhancing the Anti-HIV Activity of β-Diketo Acids.
Integrase Inhibitor Prodrugs: Approaches to Enhancing the Anti-HIV Activity of β-Diketo Acids.
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DOI：
10.3390/molecules200712623
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发表时间：
2015-07-13
期刊：
影响因子：
--
通讯作者：
Okello M
中科院分区：
文献类型：
--
作者：
Nair V;Okello M
HIV整合酶编码于HIV pol基因的3′-末端，是HIV复制所必需的。这种酶催化HIV DNA与人类DNA的结合，这代表了HIV感染的“不归路”。整合酶是发现抗HIV药物的重要靶点。这篇综述文章主要集中在整合酶抑制剂的设计，β-二酮酸构建在吡啶酮支架。这些化合物的合成方法进行了讨论。将链转移（ST）步骤的整合酶抑制数据与体外抗HIV数据进行比较。审查还审查了ST酶学数据和抗HIV检测结果之间缺乏相关性的问题。由于这种断开似乎是与渗透性相关的问题，因此设计并合成了这些抑制剂的前药。前药显著改善了抗HIV活性数据。例如，对于化合物96，抗HIV活性（EC 50）从该二酮酸的500 nM提高到其前药116的9 nM。此外，96的IC 50和IC 90 ST酶学数据（分别为6 nM和97 nM）与其前药116的EC 50和EC 90抗HIV数据（分别为9 nM和94 nM）之间存在良好的相关性。最后，证实前药116在细胞中迅速水解为活性化合物96。
HIV integrase, encoded at the 3′-end of the HIV pol gene, is essential for HIV replication. This enzyme catalyzes the incorporation of HIV DNA into human DNA, which represents the point of “no-return” in HIV infection. Integrase is a significant target in anti-HIV drug discovery. This review article focuses largely on the design of integrase inhibitors that are β-diketo acids constructed on pyridinone scaffolds. Methodologies for synthesis of these compounds are discussed. Integrase inhibition data for the strand transfer (ST) step are compared with in vitro anti-HIV data. The review also examines the issue of the lack of correlation between the ST enzymology data and anti-HIV assay results. Because this disconnect appeared to be a problem associated with permeability, prodrugs of these inhibitors were designed and synthesized. Prodrugs dramatically improved the anti-HIV activity data. For example, for compound, 96, the anti-HIV activity (EC50) improved from 500 nM for this diketo acid to 9 nM for its prodrug 116. In addition, there was excellent correlation between the IC50 and IC90 ST enzymology data for 96 (6 nM and 97 nM, respectively) and the EC50 and EC90 anti-HIV data for its prodrug 116 (9 nM and 94 nM, respectively). Finally, it was confirmed that the prodrug 116 was rapidly hydrolyzed in cells to the active compound 96.
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影响因子：
3.6
作者：
Jiang, XH;Song, LD;Long, YQ
通讯作者：
Long, YQ
影响因子：
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作者：
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DOI：
10.1073/pnas.96.23.13040
发表时间：
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影响因子：
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