HIV-1 RNase H: Recent Progress in an Exciting, yet Little Explored, Drug Target

Tramontano, Enzo

doi:10.2174/138955706777435733

Cited by 34 publications

(27 citation statements)

References 63 publications

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“…Alanine substitutions were introduced into the p66 HIV-1 RT subunit, using the QuikChange protocol (Agilent Technologies, Santa Clara, CA), in a p(His) 6 -tagged p66/p51 HIV-1HXB2 RT-prot plasmid kindly provided by Stuart Le Grice (NCI Frederick).…”

Section: Methodsmentioning

confidence: 99%

“…(His) 6 tagged p66/p51 HIV-1 RTs were expressed in Escherichia coli strain M15 containing the p6HRT-prot vector and grown to an optical density at 600 nm (OD 600 ) of 0.7, and expression was induced for 4 h with isopropyl ␤-D-1-thiogalactopyranoside (IPTG) at 1.7 mM. Protein purification was carried out with a BioLogic LP system (Bio-Rad) with a combination of immobilized metal ion affinity chromatography and ion-exchange chromatography.…”

Section: Methodsmentioning

confidence: 99%

“…This RNA removal is performed by the RT-associated RNase H function through a sequence of highly specific hydrolytic events. Since the RNase H function is essential for viral replication (5), it has been explored as a drug target, and a number of RNase H inhibitors (RHIs) have been reported (6)(7)(8). RHIs can be classified based on their binding sites, i.e., (i) RHIs that coordinate the two Mg 2ϩ catalytic cofactors at the RNase H active site, such as N-hydroxyimides (9), hydroxytropolones (10), hydroxypyrimidines (11), naphthyridinones (12), nitrofuran-2-carboxylic acid carbamoylmethyl esters (13), hydroxyquinolinones (14), and thiocarbamates and triazoles (15), or (ii) allosteric RHIs, such as vinylogous ureas (16), thienopyrimidinones (17), hydrazones (18), anthraquinones (19), isatines (20,21), and propenones (22).…”

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confidence: 99%

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Identification of Highly Conserved Residues Involved in Inhibition of HIV-1 RNase H Function by Diketo Acid Derivatives

Corona

Leva

Thierry

et al. 2014

Antimicrob Agents Chemother

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Identification of Highly Conserved Residues Involved in Inhibition of HIV-1 RNase H Function by Diketo Acid Derivatives

Corona

Leva

Thierry

et al. 2014

Antimicrob Agents Chemother

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“…During the last 10 years, several classes of HIV-1 RHIs have been identified (12)(13)(14)(15). The design of potent RHIs has proven difficult due to the open morphology of the RNase H active site (16) and the limited number of available RNase H crystal structures in complex with inhibitors (17)(18)(19)(20)(21).…”

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confidence: 99%

Inhibition of Foamy Virus Reverse Transcriptase by Human Immunodeficiency Virus Type 1 RNase H Inhibitors

Corona

Schneider

Schweimer

et al. 2014

Antimicrob Agents Chemother

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bRNase H plays an essential role in the replication of human immunodeficiency virus type 1 (HIV-1). Therefore, it is a promising target for drug development. However, the identification of HIV-1 RNase H inhibitors (RHIs) has been hampered by the open morphology of its active site, the limited number of available RNase H crystal structures in complex with inhibitors, and the fact that, due to the high concentrations of Mg 2؉ needed for protein stability, HIV-1 RNase H is not suitable for nuclear magnetic resonance (NMR) inhibitor studies. We recently showed that the RNase H domains of HIV-1 and prototype foamy virus (PFV) reverse transcriptases (RTs) exhibit a high degree of structural similarity. Thus, we examined whether PFV RNase H can serve as an HIV-1 RNase H model for inhibitor interaction studies. Five HIV-1 RHIs inhibited PFV RNase H activity at low-micromolar concentrations similar to those of HIV-1 RNase H, suggesting pocket similarity of the RNase H domains. NMR titration experiments with the PFV RNase H domain and the RHI RDS1643 (6-[1-(4-fluorophenyl)methyl-1H-pyrrol-2-yl)]-2,4-dioxo-5-hexenoic acid ethyl ester) were performed to determine its binding site. Based on these results and previous data, in silico docking analysis showed a putative RDS1643 binding region that reaches into the PFV RNase H active site. Structural overlays were performed with HIV-1 and PFV RNase H to propose the RDS1643 binding site in HIV-1 RNase H. Our results suggest that this approach can be used to establish PFV RNase H as a model system for HIV-1 RNase H in order to identify putative inhibitor binding sites in HIV-1 RNase H.

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“…Defective mutations of two key residues (E478Q and H539F) in the RNase H domain induce a marked reduction in viral proliferation [15], thus making HIV-RH an attractive chemotherapeutical target for anti-HIV drugs [16,17]. 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.…”

Section: Introductionmentioning

confidence: 99%

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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HIV-1 RNase H: Recent Progress in an Exciting, yet Little Explored, Drug Target

Cited by 34 publications

References 63 publications

Identification of Highly Conserved Residues Involved in Inhibition of HIV-1 RNase H Function by Diketo Acid Derivatives

Identification of Highly Conserved Residues Involved in Inhibition of HIV-1 RNase H Function by Diketo Acid Derivatives

Inhibition of Foamy Virus Reverse Transcriptase by Human Immunodeficiency Virus Type 1 RNase H 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

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