2,3-Dihydro-6,7-dihydroxy-1H-isoindol-1-one-Based HIV-1 Integrase Inhibitors

Zhao, Xue Zhi; Семенова, Е. А.; Vu, B. Christie; Maddali, Kasthuraiah; Marchand, Christophe; Hughes, Stephen H.; Pommier, ﻿Yves; Burke, Terrence R.

doi:10.1021/jm070715d

Cited by 50 publications

(77 citation statements)

References 34 publications

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“…Because these compounds were originally designed as inhibitors of the HIV IN, a DDE recombinase (19), and because there is evidence that ICP8 is involved in recombination (13, 14), we hypothesized that the compounds might inhibit homologous recombination in HSV-infected cells. To test the effect of XZ45 on HSV recombination during viral replication, we coinfected HEp-2 cells with two HSV mutant viruses, HSV-1 8LacZ ( U L 29 gene lacZ fusion) and HSV-1 hr 99 ( U L 5 gene lacZ insertion) mutant viruses in the presence of increasing concentrations of either XZ45 or the viral DNA polymerase inhibitor phosphonoacetic acid (PAA), the latter as a control for inhibition of viral DNA replication, to inhibit viral replication to various extents.…”

Section: Resultsmentioning

confidence: 99%

HIV Integrase Inhibitors Block Replication of Alpha-, Beta-, and Gammaherpesviruses

Yan

Bryant

Gregory

et al. 2014

mBio

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The catalytic site of the HIV integrase is contained within an RNase H-like fold, and numerous drugs have been developed that bind to this site and inhibit its activity. Herpes simplex virus (HSV) encodes two proteins with potential RNase H-like folds, the infected cell protein 8 (ICP8) DNA-binding protein, which is necessary for viral DNA replication and exhibits recombinase activity in vitro, and the viral terminase, which is essential for viral DNA cleavage and packaging. Therefore, we hypothesized that HIV integrase inhibitors might also inhibit HSV replication by targeting ICP8 and/or the terminase. To test this, we evaluated the effect of 118-D-24, a potent HIV integrase inhibitor, on HSV replication. We found that 118-D-24 inhibited HSV-1 replication in cell culture at submillimolar concentrations. To identify more potent inhibitors of HSV replication, we screened a panel of integrase inhibitors, and one compound with greater anti-HSV-1 activity, XZ45, was chosen for further analysis. XZ45 significantly inhibited HSV-1 and HSV-2 replication in different cell types, with 50% inhibitory concentrations that were approximately 1 µM, but exhibited low cytotoxicity, with a 50% cytotoxic concentration greater than 500 µM. XZ45 blocked HSV viral DNA replication and late gene expression. XZ45 also inhibited viral recombination in infected cells and ICP8 recombinase activity in vitro. Furthermore, XZ45 inhibited human cytomegalovirus replication and induction of Kaposi’s sarcoma herpesvirus from latent infection. Our results argue that inhibitors of enzymes with RNase H-like folds may represent a general antiviral strategy, which is useful not only against HIV but also against herpesviruses.

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Section: Resultsmentioning

confidence: 99%

HIV Integrase Inhibitors Block Replication of Alpha-, Beta-, and Gammaherpesviruses

Yan

Bryant

Gregory

et al. 2014

mBio

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“…The HIV-1 vector pNLNgoMIVR Ϫ ⌬Env.LUC was described previously (Zhao et al, 2008). The IN coding sequence subcloned between the KpnI and SalI sites of pBluescript II KS(ϩ) was mutagenized using the QuikChange procedure (Stratagene, La Jolla, CA).…”

Section: Methodsmentioning

confidence: 99%

Structural and Functional Analyses of the Second-Generation Integrase Strand Transfer Inhibitor Dolutegravir (S/GSK1349572)

Hare¹,

Smith²,

Métifiot³

et al. 2011

Mol Pharmacol

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Raltegravir (RAL) and related HIV-1 integrase (IN) strand transfer inhibitors (INSTIs) efficiently block viral replication in vitroand suppress viremia in patients. These small molecules bind to the IN active site, causing it to disengage from the deoxyadenosine at the 3Ј end of viral DNA. The emergence of viral strains that are highly resistant to RAL underscores the pressing need to develop INSTIs with improved resistance profiles. Herein, we show that the candidate second-generation drug dolutegravir (DTG, S/GSK1349572) effectively inhibits a panel of HIV-1 IN variants resistant to first-generation INSTIs. To elucidate the structural basis for the increased potency of DTG against RAL-resistant INs, we determined crystal structures of wild-type and mutant prototype foamy virus intasomes bound to this compound. The overall IN binding mode of DTG is strikingly similar to that of the tricyclic hydroxypyrrole MK-2048. Both second-generation INSTIs occupy almost the same physical space within the IN active site and make contacts with the ␤4 -␣2 loop of the catalytic core domain. The extended linker region connecting the metal chelating core and the halobenzyl group of DTG allows it to enter farther into the pocket vacated by the displaced viral DNA base and to make more intimate contacts with viral DNA, compared with those made by RAL and other INSTIs. In addition, our structures suggest that DTG has the ability to subtly readjust its position and conformation in response to structural changes in the active sites of RAL-resistant INs.

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“…Antiviral assays and mutant viruses. Vesicular stomatitis virus glycoprotein G (VSV-G)-pseudotyped HIV particles were obtained by cotransfection of 293 cells with pNLNgoMIVR Ϫ ⌬Env.LUC (derived from pNL4-3 by disruption of env and allowing expression of luciferase) and pCMV-VSV-G (encoding for VSV-G) and used to infect HOS cells as previously described (23). Mutant viruses were produced by site-directed mutagenesis of pNLNgoMIVR Ϫ ⌬Env.LUC.…”

Section: Methodsmentioning

confidence: 99%