Emerging pipeline drugs for hepatitis B infection

Cox, Natravis R.; Tillmann, Hans L.

doi:10.1517/14728214.2011.646260

Cited by 24 publications

(26 citation statements)

References 89 publications

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“…HBV kills over 600,000 patients annually (Ganem and Prince, 2004; Lavanchy, 2004; Shepard et al, 2006; Sorrell et al, 2009) and chronically infects up to 350 million people worldwide. Therapy primarily employs nucleos(t)ide analog drugs that suppress the virus to near or below the limit of detection but only rarely cure the infection (Cox and Tillmann, 2011; Kwon and Lok, 2011; Marcellin et al, 2008; van Bommel et al, 2010; Woo et al, 2010; Wursthorn et al, 2010). Failure to eliminate HBV is in part due to incomplete suppression of viral genomic synthesis, leading to ongoing infection of new cells and maintenance of the viral genome in infected cells (Coffin et al, 2011; Zoulim, 2004).…”

Section: Introductionmentioning

confidence: 99%

Purification and enzymatic characterization of the hepatitis B virus ribonuclease H, a new target for antiviral inhibitors

et al. 2016

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Hepatitis B virus (HBV) reverse transcription requires coordinated function of the reverse transcriptase and ribonuclease H (RNaseH) activities of the viral polymerase protein. The reverse transcriptase has been biochemically characterized, but technical difficulties have prevented both assessment of the RNaseH and development of high throughput inhibitor screens against the RNaseH. Expressing the HBV RNaseH domain with both maltose binding protein and hexahistidine tags led to stable, high-level accumulation of the RNaseH in bacteria. Nickel-affinity purification in the presence of Mg2+ and ATP removed co-purifying bacterial chaperones and yielded nearly pure monomeric recombinant enzyme. The endonucleolytic RNaseH activity required an DNA:RNA duplex ≥14 nt, could not tolerate a stem-loop in either the RNA or DNA strands, and could tolerate a nick in the DNA strand but not a gap. The RNaseH had no obvious sequence specificity or positional dependence within the RNA, and it cut the RNA at multiple positions even within the minimal 14 nt duplex. The RNaseH also possesses a processive 3’-5’ exoribonuclease activity that is slower than the endonucleolytic reaction. These results are consistent with the HBV reverse transcription mechanism that features an initial endoribonucleolytic cut, 3’-5’ degradation of RNA, and a sequence-independent terminal RNA cleavage. These data provide support for ongoing anti-RNaseH drug discovery efforts.

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Section: Introductionmentioning

confidence: 99%

Purification and enzymatic characterization of the hepatitis B virus ribonuclease H, a new target for antiviral inhibitors

et al. 2016

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“…A pproximately 350 to 400 million people worldwide are chronically infected with hepatitis B virus (HBV), a condition that can lead to cirrhosis, hepatocellular carcinoma, and death (1)(2)(3)(4)(5). Current HBV treatment options include only certain nucleoside reverse transcriptase inhibitors (NRTIs) and the innate immune modulator, interferon alpha (1)(2)(3)(4)(5)(6).…”

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confidence: 99%

“…Current HBV treatment options include only certain nucleoside reverse transcriptase inhibitors (NRTIs) and the innate immune modulator, interferon alpha (1)(2)(3)(4)(5)(6). Interferon has only limited efficacy in patients and has many adverse side effects.…”

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confidence: 99%

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3-Hydroxypyrimidine-2,4-Diones as Novel Hepatitis B Virus Antivirals Targeting the Viral Ribonuclease H

Huber

Michailidis

Tang

et al. 2017

Antimicrob Agents Chemother

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Hepatitis B virus (HBV) RNase H (RNH) is an appealing therapeutic target due to its essential role in viral replication. RNH inhibitors (RNHIs) could help to more effectively control HBV infections. Here, we report 3-hydroxypyrimidine-2,4-diones as novel HBV RNHIs with antiviral activity. We synthesized and tested 52 analogs and found 4 that inhibit HBV RNH activity in infected cells. Importantly, 2 of these compounds inhibited HBV replication in the low micromolar range. KEYWORDS RNase H, antiviral agents, hepatitis B virusA pproximately 350 to 400 million people worldwide are chronically infected with hepatitis B virus (HBV), a condition that can lead to cirrhosis, hepatocellular carcinoma, and death (1-5). Current HBV treatment options include only certain nucleoside reverse transcriptase inhibitors (NRTIs) and the innate immune modulator, interferon alpha (1-6). Interferon has only limited efficacy in patients and has many adverse side effects. NRTIs can effectively control virus production and disease progression, but they do not clear the infection. Accordingly, HBV-infected individuals currently require lifelong treatment that can be very costly and that has the potential for adverse side effects due to long-term administration of a therapeutic agent (1-6).HBV replicates through a pregenomic RNA (pgRNA) intermediate that is converted to the circular, partially double-stranded DNA genome by the viral polymerase, which has priming, reverse transcriptase, and RNase H (RNH) activities. RNH activity degrades the pgRNA during production of the negative-sense DNA strand, allowing for synthesis of the positive-sense DNA strand. The abolishment of RNH activity results in replicationincompetent viruses (7-11), suggesting that HBV RNH represents a potential drug target. To date, ␤-thujaplicinol, naphthyridinones, ␣-hydroxylated tropolones, and N-hydroxyisoquinolinediones have shown activity against HBV replication as RNH inhibitors (RNHIs) (7, 10-13). We report here that 3-hydroxypyrimidine-2,4-diones (HPDs) are novel HBV RNHIs with inhibitory activity against fully infectious HBV.Previously reported HBV RNHIs were discovered by testing known inhibitors of HIV-1 RNH and integrase, which have similar enzymatic mechanisms. Such compounds act by chelating the two metal cofactors that are coordinated to the catalytic RNH active site

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“…11,12 Given the severe long-term consequences of childhood CHB and recent reported improvements in treatment. 13,14 it is important to define the burden of disease to develop public health strategies to identify children with CHB, prevent future cases and direct services to provide specialist care where it is most needed. This study, therefore, aimed to estimate the prevalence of childhood CHB in England using 2 independent data sources and to describe the characteristics of children with CHB under specialist care.…”

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confidence: 99%

Epidemiology and Clinical Features of Childhood Chronic Hepatitis B Infection Diagnosed in England

Ladhani¹,

Flood²,

Amirthalingam³

et al. 2014

Pediatric Infectious Disease Journal

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Emerging pipeline drugs for hepatitis B infection

Cited by 24 publications

References 89 publications

Purification and enzymatic characterization of the hepatitis B virus ribonuclease H, a new target for antiviral inhibitors

Purification and enzymatic characterization of the hepatitis B virus ribonuclease H, a new target for antiviral inhibitors

3-Hydroxypyrimidine-2,4-Diones as Novel Hepatitis B Virus Antivirals Targeting the Viral Ribonuclease H

Epidemiology and Clinical Features of Childhood Chronic Hepatitis B Infection Diagnosed in England

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