ArticleAntiviral research2014
Hepatitis B virus replication is blocked by a 2-hydroxyisoquinoline-1,3(2H,4H)-dione (HID) inhibitor of the viral ribonuclease H activity.
Article in Antiviral research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 67 citations in OpenAlex.
- Hepatitis B virus ribonuclease H inhibitors: Coming of age?Antiviral research · 2026Review
- Article
- Identification and assessment of the 1,6-dihydroxy-pyridin-2-one moiety as privileged scaffold for HBV ribonuclease H inhibition.Antiviral research · 2024Article
- In Vitro Enzymatic and Cell Culture-Based Assays for Measuring Activity of HBV Ribonuclease H Inhibitors.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Antiviral Evaluation of Dispirotripiperazines against Hepatitis B Virus.Journal of medicinal chemistry · 2023Article
- Targeting Metalloenzymes: The "Achilles' Heel" of Viruses and Parasites.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Article
- Efficient Inhibition of Hepatitis B Virus (HBV) Replication and cccDNA Formation by HBV Ribonuclease H Inhibitors during Infection.Antimicrobial agents and chemotherapy · 2021Article
- Recent Advances in Hepatitis B Treatment.Pharmaceuticals (Basel, Switzerland) · 2021Review
- New Approaches to the Treatment of Chronic Hepatitis B.Journal of clinical medicine · 2020Review
- 3,7-Dihydroxytropolones Inhibit Initiation of Hepatitis B Virus Minus-Strand DNA Synthesis.Molecules (Basel, Switzerland) · 2020Article
- HBV replication inhibitors.Antiviral research · 2020Review
- Amide-containing α-hydroxytropolones as inhibitors of hepatitis B virus replication.Antiviral research · 2020Article
- Chemical Approaches to Inhibiting the Hepatitis B Virus Ribonuclease H.ACS infectious diseases · 2019Review
- Inhibition of HBV replication by N-hydroxyisoquinolinedione and N-hydroxypyridinedione ribonuclease H inhibitors.Antiviral research · 2019Article
- Endonuclease Activity Inhibition of the NS1 Protein of Parvovirus B19 as a Novel Target for Antiviral Drug Development.Antimicrobial agents and chemotherapy · 2019Article
- Development of Direct-acting Antiviral and Host-targeting Agents for Treatment of Hepatitis B Virus Infection.Gastroenterology · 2019Review
- Rosmarinic acid is a novel inhibitor for Hepatitis B virus replication targeting viral epsilon RNA-polymerase interaction.PloS one · 2018Article
- Efficacy of hepatitis B virus ribonuclease H inhibitors, a new class of replication antagonists, in FRG human liver chimeric mice.Antiviral research · 2018Article
- Efficacy and cytotoxicity in cell culture of novel α-hydroxytropolone inhibitors of hepatitis B virus ribonuclease H.Antiviral research · 2017Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Nucleos(t)ide analog drugs profoundly suppress Hepatitis B virus (HBV) replication but rarely cure the infection, so therapy is usually life-long. The nucleos(t)ide analogs inhibit the viral DNA polymerase and often push HBV to the brink of extinction, so it may be possible to eradicate HBV by suppressing HBV replication further. The HBV ribonuclease H (RNaseH) is a logical new drug target because it is the second of only two viral enzymes essential for viral replication. We recently developed a low throughput screening pipeline for inhibitors of the HBV RNaseH and viral replication. Here, we screened a series of twenty-three nitrogen-based polyoxygenated heterocycles including sixteen 2-hydroxyisoquinoline-1,3(2H,4H)-dione derivatives for anti-HBV RNaseH activity. Nine compounds inhibited the HBV RNaseH, but activity was marginal for eight of them. Compound #1 [2-hydroxyisoquinoline-1,3(2H,4H)-dione, HID] was the best hit with an IC50 of 28.1μM and an EC50 of 4.2μM. It preferentially suppressed accumulation of the viral plus-polarity DNA strand in replication inhibition assays, indicating that replication was blocked due to suppression of HBV RNaseH activity. It had a CC50 of 75μM, yielding a therapeutic index of ∼18. The EC50 value was 7-fold lower than the IC50, possibly due to cellular retention or metabolism of the compound, or higher affinity for the full-length enzyme than the recombinant form used for screening. These data indicate that the 2-hydroxyisoquinoline-1,3(2H,4H)-diones will have different structure-activity relationships for the HBV and HIV RNaseHs. Therefore, HID compounds may provide a foundation for development of more effective RNaseH inhibitors of HBV replication.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.