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Literature summary for 3.1.26.4 extracted from

  • Edwards, T.C.; Mani, N.; Dorsey, B.; Kakarla, R.; Rijnbrand, R.; Sofia, M.J.; Tavis, J.E.
    Inhibition of HBV replication by N-hydroxyisoquinolinedione and N-hydroxypyridinedione ribonuclease H inhibitors (2019), Antiviral Res., 164, 70-80 .
    View publication on PubMed

Application

Application Comment Organism
drug development the HBV ribonuclease H (RNaseH) as an antiviral drug target Hepatitis B virus

Cloned(Commentary)

Cloned (Comment) Organism
recombinant expression of His-tagged HBV ribonuclease H1 in Escherichia coli Hepatitis B virus
recombinant expression of His-tagged human ribonuclease H1 in Escherichia coli Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
1,6-dihydroxy-4-methyl-5-(N-phenoxyethanimidoyl)pyridin-2(1H)-one
-
Hepatitis B virus
1,6-dihydroxy-4-methyl-5-(N-phenoxyethanimidoyl)pyridin-2(1H)-one
-
Homo sapiens
1,6-dihydroxy-4-methyl-5-[N-[(4-methylphenyl)methoxy]ethanimidoyl]pyridin-2(1H)-one
-
Hepatitis B virus
1,6-dihydroxy-5-[N-[(2-methoxyphenyl)methoxy]ethanimidoyl]-4-methylpyridin-2(1H)-one
-
Hepatitis B virus
1,6-dihydroxy-5-[N-[(2-methoxyphenyl)methoxy]ethanimidoyl]-4-methylpyridin-2(1H)-one
-
Homo sapiens
1,6-dihydroxy-5-[N-[(4-methoxyphenyl)methoxy]ethanimidoyl]-4-methylpyridin-2(1H)-one
-
Hepatitis B virus
1,6-dihydroxy-5-[N-[(4-methoxyphenyl)methoxy]ethanimidoyl]-4-methylpyridin-2(1H)-one
-
Homo sapiens
5-[N-(4-fluorophenoxy)ethanimidoyl]-1,6-dihydroxy-4-methylpyridin-2(1H)-one
-
Hepatitis B virus
5-[N-(4-fluorophenoxy)ethanimidoyl]-1,6-dihydroxy-4-methylpyridin-2(1H)-one
-
Homo sapiens
5-[N-(benzyloxy)ethanimidoyl]-1,6-dihydroxy-4-methylpyridin-2(1H)-one
-
Hepatitis B virus
5-[N-[(2-aminophenyl)methoxy]ethanimidoyl]-1,6-dihydroxy-4-methylpyridin-2(1H)-one
-
Hepatitis B virus
5-[N-[(2-aminophenyl)methoxy]ethanimidoyl]-1,6-dihydroxy-4-methylpyridin-2(1H)-one
-
Homo sapiens
5-[N-[(2-fluorophenyl)methoxy]ethanimidoyl]-1,6-dihydroxy-4-methylpyridin-2(1H)-one
-
Hepatitis B virus
5-[N-[(2-fluorophenyl)methoxy]ethanimidoyl]-1,6-dihydroxy-4-methylpyridin-2(1H)-one
-
Homo sapiens
5-[N-[(4-fluorophenyl)methoxy]ethanimidoyl]-1,6-dihydroxy-4-methylpyridin-2(1H)-one
-
Hepatitis B virus
5-[N-[(4-fluorophenyl)methoxy]ethanimidoyl]-1,6-dihydroxy-4-methylpyridin-2(1H)-one
-
Homo sapiens
alpha-hydroxytropolones
-
Hepatitis B virus
ethyl 6-hydroxy-2-methoxy-5,7-dioxo-5,6,7,8-tetrahydro-1,6-naphthyridine-8-carboxylate
-
Hepatitis B virus
ethyl 6-hydroxy-2-methoxy-5,7-dioxo-5,6,7,8-tetrahydro-1,6-naphthyridine-8-carboxylate
-
Homo sapiens
methyl 7-benzamido-2-hydroxy-1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate
-
Homo sapiens
additional information inhibition of hepatitis B virus (HBV) replication by alpha-tropolone, N-hydroxyisoquinolinedione, and N-hydroxypyridinedione ribonuclease H inhibitors. Three compound classes, the alpha-hydroxytropolones, N-hydroxyisoquinolinediones, and N-hydroxypyridinediones are found by inhibitor screening, that suppress viral replication in cells by blocking the HBV RNaseH. These compounds preferentially suppress the plus-polarity DNA strands, induce truncation of the minus-polarity DNA strands, and cause accumulation of extensive RNA:DNA heteroduplexes in capsids as expected from their inhibition of the RNaseH. Seven N-hydroxyisoquinolinediones inhibit HBV replication, but the therapeutic indexes does not improve over what was reported. All nine of the N-hydroxypyridinedioness inhibit HBV replication. The N-hydroxypyridinedione compound class holds potential for antiviral discovery. No inhibition by 7-benzamido-N,N-diethyl-2-hydroxy-1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and methyl 7-benzamido-2-hydroxy-1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate. Determination of cellular toxicity and EC50 values for HBV replication inhibition in presence of DNA for the inhibitor compounds, overview. Comparison with effects on the human enzyme Hepatitis B virus
additional information alpha-tropolone, N-hydroxyisoquinolinedione, and N-hydroxypyridinedione ribonuclease H inhibitors are tested against human RNase H compared to hepatitis B virus RNase H. Replication inhibition efficacy and cytotoxicity, overview. No or poor inhibition by 7-benzamido-N,N-diethyl-2-hydroxy-1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, 1,6-dihydroxy-4-methyl-5-[N-[(4-methylphenyl)methoxy]ethanimidoyl]pyridin-2(1H)-one, N-(4-fluorophenyl)-6-hydroxy-2-methoxy-5,7-dioxo-5,6,7,8-tetrahydro-1,6-naphthyridine-8-carboxamide, N-[(4-fluorophenyl)methyl]-2,6-dihydroxy-5,7-dioxo-5,6,7,8-tetrahydro-1,6-naphthyridine-8-carboxamide, and N-(4-chlorophenyl)-6-hydroxy-2-methoxy-5,7-dioxo-5,6,7,8-tetrahydro-1,6-naphthyridine-8-carboxamide Homo sapiens
N-(4-chlorophenyl)-6-hydroxy-2-methoxy-5,7-dioxo-5,6,7,8-tetrahydro-1,6-naphthyridine-8-carboxamide
-
Hepatitis B virus
N-(4-fluorophenyl)-6-hydroxy-2-methoxy-5,7-dioxo-5,6,7,8-tetrahydro-1,6-naphthyridine-8-carboxamide
-
Hepatitis B virus
N-hydroxyisoquinolinedione
-
Homo sapiens
N-hydroxyisoquinolinediones
-
Hepatitis B virus
N-hydroxypyridinedione
-
Homo sapiens
N-hydroxypyridinediones
-
Hepatitis B virus
N-[(4-fluorophenyl)methyl]-2,6-dihydroxy-5,7-dioxo-5,6,7,8-tetrahydro-1,6-naphthyridine-8-carboxamide
-
Hepatitis B virus

Organism

Organism UniProt Comment Textmining
Hepatitis B virus
-
HBV
-
Homo sapiens O60930
-
-

Purification (Commentary)

Purification (Comment) Organism
recombinant His-tagged HBV ribonuclease H1 from Escherichia coli by nickel affinity chromatography Hepatitis B virus
recombinant His-tagged human ribonuclease H1 from Escherichia coli by nickel affinity chromatography Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
additional information hepatitis B virus propagation in HepBHAe82, HepDES19, and HepDE19 cell lines, overview. HepDES19/HepDE19 cells are HepG2 (human hepatoblastoma) cell line derivatives stably transfected with an HBV genotype D genome under the control of a tetracycline-repressible promoter. HepBHAe82 cell line is a HBV cell culture system is similar to the HepDES19 but it has an in-frame HA epitope tag in the N-terminal coding sequence of HBeAg in the HBV transgene, without disrupting any cis-elements critical for HBV replication, cccDNA transcription, and HA-HBeAg secretion Hepatitis B virus
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
additional information cleavage of RNA:DNA hybrid substrate Hepatitis B virus ?
-
?
additional information cleavage of RNA:DNA hybrid substrate Homo sapiens ?
-
?

Synonyms

Synonyms Comment Organism
huRNaseH1
-
Homo sapiens
ribonuclease H
-
Hepatitis B virus
ribonuclease H
-
Homo sapiens
RNaseH
-
Hepatitis B virus
RNaseH
-
Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
37
-
assay at Hepatitis B virus
37
-
assay at Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
8
-
assay at Hepatitis B virus
8
-
assay at Homo sapiens

General Information

General Information Comment Organism
malfunction inhibition of hepatitis B virus (HBV) replication by N-hydroxyisoquinolinedione and N-hydroxypyridinedione ribonuclease H inhibitors. Blocking the HBV RNaseH activity prevents removal of the RNA strand from the minus-polarity DNA strand, resulting in an accumulation of RNA:DNA heteroduplexes Hepatitis B virus
physiological function the endonucleolytic RNaseH activity (EC 3.1.26.4) requires an DNA:RNA duplex 14 nt or more and cannot tolerate a stem-loop in either the RNA or DNA strands. It tolerates a nick in the DNA strand but not a gap. The RNaseH has no obvious sequence specificity or positional dependence within the RNA, and it cuts the RNA at multiple positions even within the minimal 14 nt duplex. The RNaseH also possesses a processive 3'-5' exoribonuclease activity (EC 3.1.13.2) that is slower than the endonucleolytic reaction. The RNaseH is one of two enzymatically active domains on the HBV polymerase that synthesizes the partially double-stranded DNA genome via reverse transcription. The reverse transcriptase (RT) domain of the polymerase protein copies the pregenomic RNA (pgRNA) template to form the minus-polarity DNA strand. The RNaseH recognizes RNA:DNA heteroduplexes that are formed during minus-polarity DNA synthesis and degrades the RNA strand. The polymerase then synthesizes the positive polarity DNA strand, but it typically arrests after making only about 50% of the plus-polarity DNA strand. Both enzymatic activities of the polymerase are required for synthesis of the HBV genome Hepatitis B virus