The concept is great, it seeks to overcome the still unsatisfying capacity of the current Polymerase inhibitors by the addition of a second fully synergistic suppressor of the RNAse H activity. This might suppress virions production finally enough to dry up the constant reinfection that still exists in even ind the patients with undetectable DNA in the blood assays.
One has to understand that the vast majority of the virions that are produced in the replication suppressed state are quickly absorbed onto neighboring hepatocytes upron their release into the intracellular hepatic space of Disse.
There they start newly infected cells, hence no drop in the cccDNA and surface antigen production, despite a daily destruction of some infected hepatocytes by a limited immune activity.
Further reduction of the invisible virion production by a secondary synergistic inhibitor would possibly dramatically reduce the ongoing spread of the infection that balances the constant slow elimination.
Well, next they have to screen a large number of compounds to select realistic candidates. Their assay does not lend itself to large scale screening yet.
Once they have a good candidate, it will still take about 5 years to come to a clinically approved new drug.
Here is the abstract;
The hepatitis B virus ribonuclease h is sensitive to inhibitors of the human immunodeficiency virus ribonuclease h and integrase enzymes.
Tavis JE, Cheng X, Hu Y, Totten M, Cao F, Michailidis E, Aurora R, Meyers MJ, Jacobsen EJ, Parniak MA, Sarafianos SG.
SourceDepartment of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America ; Saint Louis University Liver Center, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America.
Nucleos(t)ide analog therapy blocks DNA synthesis by the hepatitis B virus (HBV) reverse transcriptase and can control the infection, but treatment is life-long and has high costs and unpredictable long-term side effects. The profound suppression of HBV by the nucleos(t)ide analogs and their ability to cure some patients indicates that they can push HBV to the brink of extinction. Consequently, more patients could be cured by suppressing HBV replication further using a new drug in combination with the nucleos(t)ide analogs. The HBV ribonuclease H (RNAseH) is a logical drug target because it is the second of only two viral enzymes that are essential for viral replication, but it has not been exploited, primarily because it is very difficult to produce active enzyme. To address this difficulty, we expressed HBV genotype D and H RNAseHs in E. coli and enriched the enzymes by nickel-affinity chromatography. HBV RNAseH activity in the enriched lysates was characterized in preparation for drug screening. Twenty-one candidate HBV RNAseH inhibitors were identified using chemical structure-activity analyses based on inhibitors of the HIV RNAseH and integrase. Twelve anti-RNAseH and anti-integrase compounds inhibited the HBV RNAseH at 10 µM, the best compounds had low micromolar IC(50) values against the RNAseH, and one compound inhibited HBV replication in tissue culture at 10 µM. Recombinant HBV genotype D RNAseH was more sensitive to inhibition than genotype H. This study demonstrates that recombinant HBV RNAseH suitable for low-throughput antiviral drug screening has been produced. The high percentage of compounds developed against the HIV RNAseH and integrase that were active against the HBV RNAseH indicates that the extensive drug design efforts against these HIV enzymes can guide anti-HBV RNAseH drug discovery. Finally, differential inhibition of HBV genotype D and H RNAseHs indicates that viral genetic variability will be a factor during drug development.
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