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

Corona, Angela; Leva, Francesco Saverio Di; Thierry, Sylvain; Pescatori, Luca; Crucitti, Giuliana Cuzzucoli; Subra, Frédéric; Delelis, Olivier; Esposito, Francesca; Rigogliuso, Giuseppe; Costi, Roberta; Cosconati, Sandro; Novellino, Ettore; Santo, Roberto Di; Tramontano, Enzo

doi:10.1128/aac.03605-14

Cited by 66 publications

(87 citation statements)

References 46 publications

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“…Although there is only one oxygen anion in the II‐26 structure that interacts with Mg 2+ , multiple additional interactions with Arg557 and His539 of such an oxygen and of the substituted benzene rings with Ala538 and Lys540 are predicted to contribute to increase the inhibitory activity of the compound. In agreement with our modeling studies, previous analyses predicted the involvement of ionic/π interactions between Arg557 and Mg 2+ ‐binding RNase H inhibitors (Poongavanam et al., ; Corona et al., ).…”

Section: Resultssupporting

confidence: 92%

Design, synthesis, and biologic evaluation of novel galloyl derivatives as HIV‐1 RNase H inhibitors

et al. 2019

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Human immunodeficiency virus (HIV) reverse transcriptase (RT)‐associated ribonuclease H (RNase H) remains as the only enzyme encoded within the viral genome not targeted by current antiviral drugs. In this work, we report the design, synthesis, and biologic evaluation of a novel series of galloyl derivatives with HIV‐1 RNase H inhibitory activity. Most of them showed IC50s at sub‐ to low‐micromolar concentrations in enzymatic assays. The most potent compound was II‐25 that showed an IC50 of 0.72 ± 0.07 μM in RNase H inhibition assays carried out with the HIV‐1BH10 RT. II‐25 was 2.8 times more potent than β‐thujaplicinol in these assays. Interestingly, II‐25 and other galloyl derivatives were also found to inhibit the HIV IN strand transfer activity in vitro. Structure–activity relationships (SAR) studies and molecular modeling analysis predict key interactions with RT residues His539 and Arg557, while providing helpful insight for further optimization of selected compounds.

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Section: Resultssupporting

confidence: 92%

Design, synthesis, and biologic evaluation of novel galloyl derivatives as HIV‐1 RNase H inhibitors

et al. 2019

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“…Moreover, spectroscopic analyses and molecular modeling studies indicated that such derivatives can mechanistically act by interfering with the two-metal ions through direct coordination of the metal cofactors in the enzyme catalytic site. This is in agreement with the behavior of diketo/triketoacid derivatives [14], but differs from what was observed for allosteric inhibitors [6,18] and dual inhibitors of RNase H and RT-associated DP activity, which were recently proposed to bind to a site close, but not coincident, to the RNase H active site [46]. Finally, calculated ADME properties and the preliminary finding that 10d displayed cellular cytotoxicity in human MT-4 cells at >7 μM, which was evaluated within the range of its inhibition concentration, predict that this compound can have desirable drug-like properties, thus making it suitable for further development.…”

Section: Discussionsupporting

confidence: 89%

Inhibitory Effect of 2,3,5,6-Tetrafluoro-4-[4-(aryl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide Derivatives on HIV Reverse Transcriptase Associated RNase H Activities

Pala

Esposito

Rogolino

et al. 2016

IJMS

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The HIV-1 ribonuclease H (RNase H) function of the reverse transcriptase (RT) enzyme catalyzes the selective hydrolysis of the RNA strand of the RNA:DNA heteroduplex replication intermediate, and represents a suitable target for drug development. A particularly attractive approach is constituted by the interference with the RNase H metal-dependent catalytic activity, which resides in the active site located at the C-terminus p66 subunit of RT. Herein, we report results of an in-house screening campaign that allowed us to identify 4-[4-(aryl)-1H-1,2,3-triazol-1-yl]benzenesulfonamides, prepared by the “click chemistry” approach, as novel potential HIV-1 RNase H inhibitors. Three compounds (9d, 10c, and 10d) demonstrated a selective inhibitory activity against the HIV-1 RNase H enzyme at micromolar concentrations. Drug-likeness, predicted by the calculation of a panel of physicochemical and ADME properties, putative binding modes for the active compounds, assessed by computational molecular docking, as well as a mechanistic hypothesis for this novel chemotype are reported.

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“…The lack of RnhA, and the presence of RnhC as the sole RNase H1 in clinically relevant mycobacterial pathogens, fortifies the case for inhibitors of the RnhC endonuclease as potential anti-tuberculosis and anti-leprosy agents. [Prior attention to RNase H as a drug target has focused primarily on inhibitors of the RNase H component of HIV reverse transcriptase as potential antivirals for treatment of AIDS (30–32). ] The M. smegmatis Δ rnh strains we have constructed, which rely on only RnhC or RnhA for growth, are suitable for cell-based screening for specific inhibitors of RnhC, i.e., by selecting small molecules that arrest growth of a rnhC + Δ rnhA strain but do not affect an rnhA + Δ rnhC strain.…”

Section: Discussionmentioning

confidence: 99%

Division of labor amongMycobacterium smegmatisRNase H enzymes: RNase H1 activity of RnhA or RnhC is essential for growth whereas RnhB and RnhA guard against killing by hydrogen peroxide in stationary phase

et al. 2016

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RNase H enzymes sense the presence of ribonucleotides in the genome and initiate their removal by incising the ribonucleotide-containing strand of an RNA:DNA hybrid. Mycobacterium smegmatis encodes four RNase H enzymes: RnhA, RnhB, RnhC and RnhD. Here, we interrogate the biochemical activity and nucleic acid substrate specificity of RnhA. We report that RnhA (like RnhC characterized previously) is an RNase H1-type magnesium-dependent endonuclease with stringent specificity for RNA:DNA hybrid duplexes. Whereas RnhA does not incise an embedded mono-ribonucleotide, it can efficiently cleave within tracts of four or more ribonucleotides in duplex DNA. We gained genetic insights to the division of labor among mycobacterial RNases H by deleting the rnhA, rnhB, rnhC and rnhD genes, individually and in various combinations. The salient conclusions are that: (i) RNase H1 activity is essential for mycobacterial growth and can be provided by either RnhC or RnhA; (ii) the RNase H2 enzymes RnhB and RnhD are dispensable for growth and (iii) RnhB and RnhA collaborate to protect M. smegmatis against oxidative damage in stationary phase. Our findings highlight RnhC, the sole RNase H1 in pathogenic mycobacteria, as a candidate drug discovery target for tuberculosis and leprosy.

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

Cited by 66 publications

References 46 publications

Design, synthesis, and biologic evaluation of novel galloyl derivatives as HIV‐1 RNase H inhibitors

Design, synthesis, and biologic evaluation of novel galloyl derivatives as HIV‐1 RNase H inhibitors

Inhibitory Effect of 2,3,5,6-Tetrafluoro-4-[4-(aryl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide Derivatives on HIV Reverse Transcriptase Associated RNase H Activities

Division of labor amongMycobacterium smegmatisRNase H enzymes: RNase H1 activity of RnhA or RnhC is essential for growth whereas RnhB and RnhA guard against killing by hydrogen peroxide in stationary phase

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