Preferential Inhibition of the Magnesium-Dependent Strand Transfer Reaction of HIV-1 Integrase by α-Hydroxytropolones

Семенова, Е. А.; Johnson, Allison A.; Marchand, Christophe; Davis, David A.; Yarchoan, Robert; Pommier, ﻿Yves

doi:10.1124/mol.105.020321

Cited by 59 publications

(47 citation statements)

References 45 publications

(50 reference statements)

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“…DNA aptamer inhibitors of RNase H can inhibit HIV-1 integrase (4), and conversely, HIV-1 RNase H can be inhibited by some diketo acid inhibitors of integrase (17,19). Recently, tropolone derivatives have been reported to inhibit both enzymes (2,5,16). These results represent a proof of concept for the dual inhibition of integrase and RNase H by structurally related compounds and provide a rationale for discovering and elucidating the mechanisms of action of inhibitors of these two enzymes.…”

Section: Madurahydroxylactone (Mhl)mentioning

confidence: 80%

Madurahydroxylactone Derivatives as Dual Inhibitors of Human Immunodeficiency Virus Type 1 Integrase and RNase H

Marchand

Beutler

Wamiru

et al. 2008

Antimicrob Agents Chemother

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A series of 29 madurahydroxylactone derivatives was evaluated for dual inhibition of human immunodeficiency virus type 1 (HIV-1) integrase and RNase H. While most of the compounds exhibited similar potencies for both enzymes, two of the derivatives showed 10-to 100-fold-higher selectivity for each enzyme, suggesting that distinct pharmacophore models could be generated. This study exemplifies the common and divergent structural requirements for the inhibition of two structurally related HIV-1 enzymes and demonstrates the importance of systematically screening for both integrase and RNase H when developing novel inhibitors.

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Section: Madurahydroxylactone (Mhl)mentioning

confidence: 80%

Madurahydroxylactone Derivatives as Dual Inhibitors of Human Immunodeficiency Virus Type 1 Integrase and RNase H

Marchand

Beutler

Wamiru

et al. 2008

Antimicrob Agents Chemother

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“…Integrase ST-selective inhibitors are being pursued for clinical development (Hazuda et al, 2004a,b;Pommier et al, 2005;Dayam et al, 2006;DeJesus et al, 2006;Semenova et al, 2006a). The naphthyridine carboximide L-870,810 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Probing HIV-1 Integrase Inhibitor Binding Sites with Position-Specific Integrase-DNA Cross-Linking Assays

Johnson¹,

Marchand²,

Patil³

et al. 2006

Mol Pharmacol

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HIV-1 integrase binds site-specifically to the ends of the viral cDNA. We used two HIV-1 integrase-DNA cross-linking assays to probe the binding sites of integrase inhibitors from different chemical families and with different strand transfer selectivities. The disulfide assay probes cross-linking between the integrase residue 148 and the 5Ј-terminal cytosine of the viral cDNA, and the Schiff base assay probes cross-linking between an integrase lysine residue and an abasic site placed at selected positions in the viral cDNA. Cross-linking interference by eight integrase inhibitors shows that the most potent cross-linking inhibitors are 3Ј-processing inhibitors, indicating that crosslinking assays probe the donor viral cDNA (donor binding site). In contrast, strand transfer-selective inhibitors provide weak cross-linking interference, consistent with their binding to a specific acceptor (cellular DNA) site. Docking and crystal structure studies illustrate specific integrase-inhibitor contacts that prevent cross-linking formation. Four inhibitors that prevented Schiff base cross-linking to the conserved 3Ј-terminal adenine position were examined for inhibition at various positions within the terminal 21 bases of the viral cDNA. Two of them selectively inhibited upper strand cross-linking, whereas the other two had a more global effect on integrase-DNA binding. These findings have implications for elucidating inhibitor binding sites and mechanisms of action. The cross-linking assays also provide clues to the molecular interactions between integrase and the viral cDNA.

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“…One of these compounds, the natural product ␤-thujaplicinol (34), is the most widely studied member of a class of troponoids called ␣-hydroxytropolones that have been identified as anticancer agents (35,36) as well as lead therapeutic agents for a number of infections, including HIV (37)(38)(39)(40)(41), HBV (42), malaria (43), and many bacteria (44). This antimicrobial activity is often attributed to the capacity of the compounds to sequester divalent cations in the active sites of dinuclear metalloenzymes, a feature arising from the three contiguous oxygen atoms on the troponoid ring (45)(46)(47). Here, 26 synthetic ␣-hydroxytropolones were screened for their capacity to inhibit HSV-1 and HSV-2 replication to assess whether ␣-hydroxytropolones may be attractive candidates for development as anti-HSV drugs.…”

mentioning

confidence: 99%

Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses

Ireland

Tavis

D’Erasmo

et al. 2016

Antimicrob Agents Chemother

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cHerpes simplex virus 1 (HSV-1) and HSV-2 remain major human pathogens despite the development of anti-HSV therapeutics as some of the first antiviral drugs. Current therapies are incompletely effective and frequently drive the evolution of drug-resistant mutants. We recently determined that certain natural troponoid compounds such as ␤-thujaplicinol readily suppress HSV-1 and HSV-2 replication. Here, we screened 26 synthetic ␣-hydroxytropolones with the goals of determining a preliminary structure-activity relationship for the ␣-hydroxytropolone pharmacophore and providing a starting point for future optimization studies. Twenty-five compounds inhibited HSV-1 and HSV-2 replication at 50 M, and 10 compounds inhibited HSV-1 and HSV-2 at 5 M, with similar inhibition patterns and potencies against both viruses being observed. The two most powerful inhibitors shared a common biphenyl side chain, were capable of inhibiting HSV-1 and HSV-2 with a 50% effective concentration (EC 50 ) of 81 to 210 nM, and also strongly inhibited acyclovir-resistant mutants. Moderate to low cytotoxicity was observed for all compounds (50% cytotoxic concentration [CC 50 ] of 50 to >100 M). Therapeutic indexes ranged from >170 to >1,200. These data indicate that troponoids and specifically ␣-hydroxytropolones are a promising lead scaffold for development as anti-HSV drugs provided that toxicity can be further minimized. Troponoid drugs are envisioned to be employed alone or in combination with existing nucleos(t)ide analogs to suppress HSV replication far enough to prevent viral shedding and to limit the development of or treat nucleos(t)ide analog-resistant mutants.

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Preferential Inhibition of the Magnesium-Dependent Strand Transfer Reaction of HIV-1 Integrase by α-Hydroxytropolones

Cited by 59 publications

References 45 publications

Madurahydroxylactone Derivatives as Dual Inhibitors of Human Immunodeficiency Virus Type 1 Integrase and RNase H

Madurahydroxylactone Derivatives as Dual Inhibitors of Human Immunodeficiency Virus Type 1 Integrase and RNase H

Probing HIV-1 Integrase Inhibitor Binding Sites with Position-Specific Integrase-DNA Cross-Linking Assays

Synthetic α-Hydroxytropolones Inhibit Replication of Wild-Type and Acyclovir-Resistant Herpes Simplex Viruses

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