The hepatitis B virus ribonuclease H as a drug target

Abstract

Chronic hepatitis B virus (HBV) infection is a leading cause of hepatitis, liver failure, and hepatocellular carcinoma. An outstanding vaccine is available; however the number of infections remains high. Current anti-HBV treatments with interferon α and nucleos(t)ide analogs clear the infection in only a small minority of patients, and either induce serious side-effects or are of very long duration. HBV is a small, enveloped DNA virus that replicates by reverse transcription via an RNA intermediate. The HBV ribonuclease H (RNaseH) is essential for viral replication, but it has not been exploited as a drug target. Recent low-throughput screening of compound classes with anti-Human Immunodeficiency Virus RNaseH activity led to identification of HBV RNaseH inhibitors in three different chemical families that block HBV replication. These inhibitors are promising candidates for development into new anti-HBV drugs. The RNaseH inhibitors may help improve treatment efficacy enough to clear the virus from the liver when used in combination with existing anti-HBV drugs and/or with other novel inhibitors under development. This article forms part of a symposium in Antiviral Research on “An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B.”

Tratamiento actual y nuevas terapias contra la infección crónica por el virus de la Hepatitis B

“…La inhibición de esta enzima está ampliamente conocida como parte del tratamiento contra el VIH, pero poco se ha estudiado sobre su uso como tratamiento para el VHB, con algunos estudios in vitro que sugieren su efectividad (43,73). El objetivo de los medicamentos que comparten este mecanismo de acción es suprimir la replicación viral para detener el reaprovisionamiento de ADNccc en el hígado, lo que permite eliminar las células infectadas por el sistema inmune o por otro medicamento concomitante (66,74).…”

New horizon for radical cure of chronic hepatitis B virus infection

“…RNase H inhibitors are also being tested, based on the specificity of HBV replication, which depends on the RNase H activity of HBV polymerase to degrade pgRNA [10] . Evaluations of selective inhibitors of HBV polymerase RNase H activity [96] suggest that they might be more effective when combined with NAs [93] . [97] .…”

Synergistic Interactions between Hepatitis B Virus RNase H Antagonists and Other Inhibitors

“…Both activities are necessary for viral replication; however, the clinically available direct-acting anti-HBV drugs target the HBV RT, whereas RNase H inhibitors are yet to be developed. Therefore, the RNase H is an attractive target for new anti-HBV drugs that may be used in combination with the NAs to increase effectiveness of treatment (15,16). Recently, we identified several promising compounds that inhibit both HBV RNase H activity and viral DNA synthesis (17)(18)(19)(20).…”