Abstract
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.
Highlights
HIV-1 integrase, which is encoded at the 3′-end of the pol gene of the human immunodeficiency virus (HIV), is a retroviral enzyme, which is required for the replication of HIV
The retroviral enzyme, HIV integrase, catalyzes the incorporation of HIV DNA into human chromosomal DNA. Inhibitors of this point of “no-return” in HIV infection are of considerable significance in anti-HIV drug discovery
This review article has focused on the issue of the lack of correlation between integrase strand transfer (ST) enzymology data (IC50) and the corresponding cellular anti-HIV EC50 data for beta-diketo acid inhibitors of integrase
Summary
HIV-1 integrase, which is encoded at the 3′-end of the pol gene of the human immunodeficiency virus (HIV), is a retroviral enzyme, which is required for the replication of HIV. The processed intasome (i.e., truncated viral DNA-integrase complex) is transported into the nucleus where the ST step takes place. After the 3′P step, the multimeric pre-integration complex of tailored viral DNA and integrase is transported through the nuclear envelope and into the nucleus where integrase catalyzes the insertion of the processed viral DNA ends into host chromosomal DNA. This ST step involves staggered nicking of chromosomal DNA and subsequent joining of each 3′-end of the recessed viral DNA to the 5′-ends of the host DNA. Of relevance is a recent report on the development of raltegravir-based prodrugs to enhance colonic absorption and to lower frequency of administration [21,22]
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