An HIV RNase H Inhibitory 1,3,4,5-Tetragalloylapiitol from the African Plant <i>Hylodendron gabunensis</i>

Takada, Kentaro; Bermingham, Alun; O’Keefe, Barry R.; Wamiru, Antony; Beutler, John A.; Grice, Stuart F. J. Le; Lloyd, John R.; Gustafson, Kirk R.; McMahon, James B.

doi:10.1021/np0702279

Cited by 21 publications

(17 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Surprisingly, even the compounds that were active against HIV-1 RNase H were not protective in the cell-based cytopathicity screen at 20 μ g/mL (data not shown), and therefore, additional follow-up studies on the compounds were not completed, including testing for reverse transcriptase activity. Potent activity in enzymatic assays but a lack of activity in the cell-based cytopathicity assay is an emerging theme for gallate esters in this assay 11, 12. That these compounds do not have activity in the cell-based screen is very different from the many small phenolic compounds with HIV-1 activity we have isolated in our laboratory over the years 13–15.…”

mentioning

confidence: 99%

HIV-1 Ribonuclease H Inhibitory Phenolic Glycosides from Eugenia hyemalis

et al. 2008

Self Cite

View full text Add to dashboard Cite

Three new galloyl arbutins, hyemalosides A-C (1-3), along with nine known compounds were isolated from the evergreen tree Eugenia hyemalis. The structures of compounds 1-3 were determined by analysis of NMR and MS data. Compounds 1-3 inhibited HIV-1 RNase H in vitro with IC 50 values of 1.46, >18, and 1.19 μM, respectively. However, in a XTT-based cell viability assay using the human T-cell line CEM-SS infected with HIV-1 RT , none of the compounds inhibited the cytopathic effect of HIV-1 infection at the highest dose tested (20 μg/mL).As part of a molecularly targeted screening program to discover drug leads from natural products, we investigated the chemistry of the evergreen tree Eugenia hyemalis L. Cambess (Myrtaceae). The organic extract of the plant showed inhibition of ribonuclease H (RNase H) enzymatic activity in a high-throughput screening assay. 1 RNase H is a second, distinct enzymatic activity of the HIV-1 reverse transcriptase protein. It is a nonspecific nuclease that is responsible for hydrolyzing the RNA strand of a RNA/DNA heteroduplex and allowing the incorporation of viral genetic information into the host cell genome. Because RNase H activity is required for viral infectivity, it is a viable target for screening for potential anti-HIV drugs, and a high-throughput fluorescence resonance energy transfer (FRET) assay 1 was developed for this purpose.Bioassay-guided fractionation of the extract led to the isolation of three new compounds, hyemalosides A-C (1-3), along with nine known compounds. The structures of the nine known compounds were determined on the basis of spectroscopic evidence and comparison with literature values. These were characterized as 2-O-galloylarbutin, 2 4-O-galloylarbutin, 2,6-di-O-galloylarbutin, 3 2,4,6-tri-O-galloylarbutin, 4 1,2,6-tri-O-galloyl-β-D-glucose, 5 kaempferol-3-O-(6-O-galloyl-β-D-glucopyranoside), 6 afzelin 2″-O-gallate, 7 afzelin 3″-Ogallate, 7 and quercitrin. 7 HREIMS of compound 1 showed a peak at m/z 727.1191 [M -H] − consistent with a molecular formula of C 33 H 28 O 19 . The 1 H NMR spectrum showed a proton doublet at δ 5.13 (J = 7.9 Hz) along with six resonances from δ 3.88 to 5.49, which were linked by COSY data and indicated a hexose moiety. Large coupling constants for the sugar ring protons (J = 7.9-9.5 Hz) indicated a series of trans diaxial couplings characteristic of glucose and also revealed that the anomeric oxygen was β-oriented.

show abstract

mentioning

confidence: 99%

HIV-1 Ribonuclease H Inhibitory Phenolic Glycosides from Eugenia hyemalis

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…Highthroughput screening of National Cancer Institute libraries of natural products also identified the hydroxytropolone ␤-thujaplicinol (7), phenolic glycosides (4), 1,3,4,5-tetragalloylaopiitol (31), and dimeric lactones (10) to be moderately potent RNase H inhibitors, with 50% inhibitory concentrations (IC 50 s) ranging from 0.25 to 1.5 M for both the HIV-1 and HIV-2 enzymes. Screening of a library of 100,000 synthetic compounds identified the vinylogous ureas 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide and N- [3-(aminocarbonyl) -4,5dimethyl-2-thienyl]-2-furancarboxamide ( Fig.…”

mentioning

confidence: 99%

Structure-Activity Analysis of Vinylogous Urea Inhibitors of Human Immunodeficiency Virus-Encoded Ribonuclease H

Chung

Wendeler

Rausch

et al. 2010

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Vinylogous ureas 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide and N-[3-(aminocarbonyl)-4,5-dimethyl-2-thienyl]-2-furancarboxamide (compounds 1 and 2, respectively) were recently identified to be modestly potent inhibitors of the RNase H activity of HIV-1 and HIV-2 reverse transcriptase (RT). Both compounds shared a 3-CONH 2 -substituted thiophene ring but were otherwise structurally unrelated, which prevented a precise definition of the pharmacophore. We have therefore examined a larger series of vinylogous ureas carrying amide, amine, and cycloalkane modifications of the thiophene ring of compound 1. While cycloheptane-and cyclohexane-substituted derivatives retained potency, cyclopentane and cyclooctane substitutions eliminated activity. In the presence of a cycloheptane ring, modifying the 2-NH 2 or 3-CONH 2 functions decreased the potency. With respect to compound 2, vinylogous ureas whose dimethylthiophene ring contained modifications of the 2-NH 2 and 3-CONH 2 functions were investigated. 2-NH 2 -modified analogs displayed potency equivalent to or enhanced over that of compound 2, the most active of which, compound 16, reflected intramolecular cyclization of the 2-NH 2 and 3-CONH 2 groups. Molecular modeling was used to define an inhibitor binding site in the p51 thumb subdomain, suggesting that an interaction with the catalytically conserved His539 of the p66 RNase H domain could underlie inhibition of RNase H activity. Collectively, our data indicate that multiple functional groups of vinylogous ureas contribute to their potencies as RNase H inhibitors. Finally, single-molecule spectroscopy indicates that vinylogous ureas have the property of altering the reverse transcriptase orientation on a model RNA-DNA hybrid mimicking initiation plus-strand DNA synthesis.Current success in treating HIV infection and AIDS can be attributed to effective combination antiretroviral therapy involving a cocktail of inhibitors directed primarily against the retroviral protease and reverse transcriptase (RT) (22). Inhibition of RT function is achieved either directly, by incorporating chain-terminating nucleoside derivatives (nucleoside RT inhibitors [NRTIs]), or indirectly, by nonnucleoside RT inhibitors (NNRTIs) that occupy a hydrophobic pocket at the base of the p66 thumb to interrupt the chemical step of DNA synthesis (25)

show abstract

Section: Diketo Acidsmentioning

confidence: 94%

“…RDS 1643 (46), inhibited the HIV-1 RNase H activity in enzyme assays with an IC 50 [18]. However, RDS 1643 (46) would not reach towards the p51 subunit as far as BTDBA, showing therefore a less favorable interaction with RT, consistently with the lower potency of RDS 1643 (46) inhibition as compared to BTDBA (45) inhibition. Therefore, even though no straight demonstration that RDS 1643 (46) inhibits the RNase H activity inside the cells has been published yet, these docking results support the claim that RDS 1643 (46) inhibits the HIV-1 replication through the selective inhibition of the RT-associated RNase H function [80].…”

Section: Diketo Acidsmentioning

confidence: 94%

HIV-1 RT-Associated RNase H Function Inhibitors: Recent Advances in Drug Development

Tramontano

Santo

2010

CMC

View full text Add to dashboard Cite

The HIV-1 genomic RNA reverse transcription is an essential step in the virus cycle carried out by the viral-coded reverse transcriptase (RT), which has two associated functions: the RNA- and DNA-dependent DNA polymerase (RDDP and DDDP) function and the ribonuclease H (RNase H) function. The RNase H function catalyzes the selective hydrolysis of the RNA strand of the RNA:DNA heteroduplex replication intermediate. The RT associated activities are both essential for HIV-1 replication and validated targets for drug development, but only the polymerase function has been widely investigated as drug target. In fact, either nucleoside or non-nucleoside RT inhibitors currently used in therapy act on the polymerase associated activity. In this review, we describe the compounds, reported up to today, which inhibit the HIV-1 RNase H function, their chemical structures, the structure-activity relationships and the mechanism of action.

show abstract

An HIV RNase H Inhibitory 1,3,4,5-Tetragalloylapiitol from the African Plant Hylodendron gabunensis

Cited by 21 publications

References 13 publications

HIV-1 Ribonuclease H Inhibitory Phenolic Glycosides from Eugenia hyemalis

HIV-1 Ribonuclease H Inhibitory Phenolic Glycosides from Eugenia hyemalis

Structure-Activity Analysis of Vinylogous Urea Inhibitors of Human Immunodeficiency Virus-Encoded Ribonuclease H

HIV-1 RT-Associated RNase H Function Inhibitors: Recent Advances in Drug Development

Contact Info

Product

Resources

About