Activity of the isolated HIV RNase H domain and specific inhibition by N-hydroxyimides

Hang, Julie Q.; Rajendran, Surendran; Yang, Yanli; Liu, Yu; In, Philippe Wong Kai; Overton, Hilary A.; Parkes, K. E. B.; Cammack, Nick; Martin, Joseph A.; Klumpp, Klaus

doi:10.1016/j.bbrc.2004.03.061

Cited by 54 publications

(64 citation statements)

References 31 publications

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“…However, the peak splitting was not observed in the Ca 2+ titration experiments. The distance between the two Mg 2+ ions in the active site is 4 Å, as shown in the crystal structure [8,10,11]. Ca 2+ has a much larger atomic radius than Mg 2+ ; therefore, it is unlikely that two Ca 2+ ions can fit simultaneously into the active site.…”

Section: Sequential Binding Of Two Mg 2+ Ions To the Active Sitementioning

confidence: 95%

“…However, there has been some controversy regarding the number of metal ions (one or two) involved in the catalysis. Crystallographic studies of both E. coli RNase H and HIV-RH have shown that the active site can bind two Mn 2+ ions separated by approximately 4 Å and the authors proposed a two-metal-ion catalytic mechanism [9,10]. The ability of HIV-RH to bind to two metal ions, either two Mn 2+ or two Mg 2+ , has also been confirmed by calorimetry and NMR, respectively [9,11].…”

Section: Introductionmentioning

confidence: 92%

“…Designing metal-chelating compounds that are able to bind two divalent metal ions at the active site is one strategy that enables the direct blocking of the active site. Small N-hydroxyimide analogs that are optimized to bind two divalent metal ions at a 4 Ǻ distance between the ions inhibit HIV-RT activity in vitro with an IC 50 < 1.0 uM [10]. Metal-chelating compounds are an important class of chemicals in pharmacological drug design, especially when targeted against proteins with metal ions at their active sites [4].…”

Section: Introductionmentioning

confidence: 99%

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Targeting Divalent Metal Ions at the Active Site of the HIV-1 RNase H Domain: NMR Studies on the Interactions of Divalent Metal Ions with RNase H and Its Inhibitors

Yan¹

2011

AJAC

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HIV-1 reverse transcriptase (RT) RNase H (HIV-RH) is a key target of anti-AIDS drugs. Metal-chelating compounds are an important class of chemicals in pharmacological drug discovery, especially in relation to HIV-RT and the highly-related HIV-integrase. The correlation between the metal-chelating properties and enzyme activities of the metal chelators is always of high scientific interest, as an understanding of this may accelerate the rational optimization of this class of inhibitors. Our NMR data show that Mg 2+ and Ca 2+ bind specifically to the active site of the RNase H domain and two Mg 2+ ions sequentially bind one molecule of RNase H. We also demonstrate here, using saturated and unsaturated tricyclic N-hydroxypyridones designed to block the active site, that the primary binding sites and affinities of divalent metal ions are correlated with the structures of the chelating motifs. Chemical shift perturbation studies of protein/metal-ion/compound ternary complexes also indicate that divalent metal ions play important roles for the specific interaction of the compounds with the RNase H active site.

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Section: Sequential Binding Of Two Mg 2+ Ions To the Active Sitementioning

confidence: 95%

Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Targeting Divalent Metal Ions at the Active Site of the HIV-1 RNase H Domain: NMR Studies on the Interactions of Divalent Metal Ions with RNase H and Its Inhibitors

Yan¹

2011

AJAC

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“…For the biological properties of the title compound, see: Parkes et al (2003); Hang et al (2004); Billamboz et al (2008). For a related structure, see: Miao et al (1995).…”

Section: Related Literaturementioning

confidence: 99%

“…The title compound is known to inhibit metalloenzymes such as influenza endonuclease (Parkes et al, 2003), HIV-1 reverse transcriptase RNase H (Hang et al, 2004), and HIV-1 integrase (Billamboz et al, 2008). Here we report the crystal structure of the title compound, which was obtained from the deprotection of 2-benzyloxyisoquinoline-1,3(2H,4H)-dione by the use of boron tribromide.…”

Section: S1 Commentmentioning

confidence: 99%

2-Hydroxyisoquinoline-1,3(2H,4H)-dione

Ishikawa

Matsuo

2013

Acta Cryst E

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Key indicators: single-crystal X-ray study; T = 100 K; mean (C-C) = 0.002 Å; R factor = 0.032; wR factor = 0.089; data-to-parameter ratio = 13.9.The title molecule, C 9 H 7 NO 3 , exists in the diketo form and the isoquinoline unit is approximately planar (r.m.s. deviation = 0.0158 Å ). In the crystal, molecules are linked into inversion dimers through pairs of O-HÁ Á ÁO hydrogen bonds and are further assembled into the (100) layers via stacking interactions [centroid-centroid distances = 3.460 (3) and 3.635 (4) Å ]. Related literature ExperimentalCrystal data Table 1 Hydrogen-bond geometry (Å , ). The authors acknowledge the University of Shizuoka for supporting this study.

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HIV Integrase

Johns

2010

Burger's Medicinal Chemistry and Drug Discovery

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Integrase (IN) is one of only three viral enzymes encoded by the human immunodeficiency virus (HIV). The enzymatic activity of IN catalyzes the “integration” of viral double‐stranded DNA into host chromatin. Several steps including assembly, nuclear import, and gap repair are involved in the overall integration process, but two distinct biochemical steps are catalyzed by IN. The first step called 3′ processing allows for water to cleave the terminal dinucleotide on the respective ends of the viral DNA. The second discreet step called strand transfer facilitates the nicking of the host DNA by the recessed 3′ hydroxyl groups of the processed viral DNA. It is this second step of strand transfer that has been the focus of the bulk share of drug discovery efforts to date and the only step successfully inhibited by compounds that all fall into a class called two‐metal chelators. The science around the integrase enzyme is presented from a high‐level view of integration as part of the retroviral replication cycle through a molecular view of the biochemistry of the integration process involving nucleic acid strands. This chapter discusses inhibition of the strand transfer process and presents the two‐metal pharmacophore model and inhibitor design. The body of this work is focused on numerous classes of two‐metal chelation inhibitors of HIV‐1 integrase including several clinical candidates. The chapter concludes with a short survey of potential next‐generation compounds that have appeared in the literature through the end of 2008.

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Activity of the isolated HIV RNase H domain and specific inhibition by N-hydroxyimides

Cited by 54 publications

References 31 publications

Targeting Divalent Metal Ions at the Active Site of the HIV-1 RNase H Domain: NMR Studies on the Interactions of Divalent Metal Ions with RNase H and Its Inhibitors

Targeting Divalent Metal Ions at the Active Site of the HIV-1 RNase H Domain: NMR Studies on the Interactions of Divalent Metal Ions with RNase H and Its Inhibitors

2-Hydroxyisoquinoline-1,3(2H,4H)-dione

HIV Integrase

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