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The Hepatitis B Virus Ribonuclease H Is Sensitive to Inhibitors of the Human Immunodeficiency Virus Ribonuclease H and Integrase Enzymes

Tavis, JE and Cheng, X and Hu, Y and Totten, M and Cao, F and Michailidis, E and Aurora, R and Meyers, MJ and Jacobsen, EJ and Parniak, MA and Sarafianos, SG (2013) The Hepatitis B Virus Ribonuclease H Is Sensitive to Inhibitors of the Human Immunodeficiency Virus Ribonuclease H and Integrase Enzymes. PLoS Pathogens, 9 (1). ISSN 1553-7366

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Abstract

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. © 2013 Tavis et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Tavis, JE
Cheng, X
Hu, Y
Totten, M
Cao, F
Michailidis, E
Aurora, R
Meyers, MJ
Jacobsen, EJ
Parniak, MAmap167@pitt.eduMAP167
Sarafianos, SG
Date: 1 January 2013
Date Type: Publication
Journal or Publication Title: PLoS Pathogens
Volume: 9
Number: 1
DOI or Unique Handle: 10.1371/journal.ppat.1003125
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Refereed: Yes
ISSN: 1553-7366
Other ID: NLM PMC3551811
PubMed Central ID: PMC3551811
PubMed ID: 23349632
Date Deposited: 14 Mar 2013 14:34
Last Modified: 05 Mar 2019 00:56
URI: http://d-scholarship.pitt.edu/id/eprint/17733

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