Molecular, Evolutionary, and Structural Analysis of the Terminal Protein Domain of Hepatitis B Virus Polymerase, a Potential Drug Target

Buhlig, Timothy S; Bowersox, Anastasia F; Braun, Daniel L; Owsley, Desiree N; James, Kortney D; Aranda, Alfredo J; Kendrick, Connor D; Skalka, Nicole A; Clark, Daniel N.

doi:10.3390/v12050570

Cited by 12 publications

(11 citation statements)

References 90 publications

(189 reference statements)

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“…The HBV Pol protein is the focus of basic research and translational research. The Viral polymerase is the target of all current HBV drug therapies (except interferon), and it is the only area that is usually sequenced during treatment escape (Rhee et al, 2010;Buhlig et al, 2020). Genetic variation resulting from recombination can allow immune escape and treatment resistance.…”

Section: Discussionmentioning

confidence: 99%

Identification of recombinants of hepatitis B virus genotypes C from Hong Kong China

Liu¹,

Tu²

2021

Afr. J. Microbiol. Res.

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Hepatitis B virus (HBV) infections severely threaten the health of the human being. Frequent recombination of HBV within or between genotypes was reported to favor the viral evolution and adaption and the recombination may cause more severe clinical symptoms. In the study, we collected genotype C HBV from five Asian countries and detected their possible recombination events by bioinformatic analysis. There are two main subtypes, C1 and C2, within the C genotypes among the collected data in the study. Subtype C1 is most prevalent in Cambodia, Bangladesh, and China, while C2 is prevalent in Japan, Indonesia, and a small part of China. Three recombination events were detected and verified from C1 genotype HBV from Hong Kong China as demonstrated by recombinant (KJ410515), ranging from 2381 to 1861 nt. Recombinant events were detected and verified by recombination analysis in the study. It is important to filter possible recombinants when using the online-genbank data to do phylogenetic analysis.

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Section: Discussionmentioning

confidence: 99%

Identification of recombinants of hepatitis B virus genotypes C from Hong Kong China

Liu¹,

Tu²

2021

Afr. J. Microbiol. Res.

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“…HBV P contains four domains: the terminal protein (TP), the spacer, the reverse transcriptase (RT) domain, and the ribonuclease H (RNaseH) domain [ 51 , 52 ]. The pgRNA binds to P via the ε -stem loop located close to its 5′-end with specific motifs in the TP, spacer, RT, and RNaseH domains to form a pgRNA-P ribonucleoprotein (RNP) complex [ 53 , 54 , 55 , 56 , 57 ]. This interaction is of great importance, as it is essential for the RNA packaging into nucleocapsids and initiation of reverse transcription [ 58 , 59 ].…”

Section: Hbv Replication Cyclementioning

confidence: 99%

Recent Advances in Hepatitis B Treatment

et al. 2021

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Hepatitis B virus infection affects over 250 million chronic carriers, causing more than 800,000 deaths annually, although a safe and effective vaccine is available. Currently used antiviral agents, pegylated interferon and nucleos(t)ide analogues, have major drawbacks and fail to completely eradicate the virus from infected cells. Thus, achieving a “functional cure” of the infection remains a real challenge. Recent findings concerning the viral replication cycle have led to development of novel therapeutic approaches including viral entry inhibitors, epigenetic control of cccDNA, immune modulators, RNA interference techniques, ribonuclease H inhibitors, and capsid assembly modulators. Promising preclinical results have been obtained, and the leading molecules under development have entered clinical evaluation. This review summarizes the key steps of the HBV life cycle, examines the currently approved anti-HBV drugs, and analyzes novel HBV treatment regimens.

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“…No experimentally determined structures exist for any domain of P despite its importance as a drug target and the unusual reverse transcription pathway it catalyzes due to protein production issues and P’s conformational plasticity. An ab initio predicted model has been proposed for the TP domain based on secondary structure predictions (24). Multiple homology models generated against retroviral RT domains exist for the RT domain of HBV P (25, 26).…”

Section: Introductionmentioning

confidence: 99%

Predicted structure of the hepatitis B virus polymerase reveals an ancient conserved protein fold

Tajwar

Bradley

Ponzar

et al. 2022

Preprint

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Hepatitis B virus (HBV) replicates by protein-primed reverse transcription. It chronically infects >250 million people, and the dominant anti-HBV drugs are nucleos(t)ide analogs targeting the viral polymerase (P). P has four domains, the terminal protein (TP) that primes DNA synthesis, a spacer, the reverse transcriptase (RT), and the ribonuclease H (RNaseH). Despite being a major drug target and catalyzing a reverse transcription pathway very different from the retroviral pathway, HBV P has resisted structural analysis for decades. Here, we exploited advances in protein structure prediction to model the structure of P. The predicted HBV RT and RNaseH domains aligned to the HIV RT-RNaseH at 3.75 A RMSD, had a nucleic acid binding groove spanning the two active sites, had DNA polymerase active site motifs in their expected positions, and accommodated two Mg++ ions in both active sites. Surprisingly, the TP domain wrapped around the RT domain, with the priming tyrosine poised over the RT active site. This model was validated using published mutational analyses, and by docking RT and RNaseH inhibitors, RNA:DNA heteroduplexes, and the HBV e RNA stem-loop that templates DNA priming into the model. The HBV P fold, including the orientation of the TP domain, was conserved among hepadnaviruses from rodents to fish and in P from a fish nackednavirus, but not in other non-retroviral RTs. Therefore, this protein fold has persisted since the hepadnaviruses diverged from nackednaviruses >400 million years ago. This model will guide drug development and mechanistic studies into P function.

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Molecular, Evolutionary, and Structural Analysis of the Terminal Protein Domain of Hepatitis B Virus Polymerase, a Potential Drug Target

Cited by 12 publications

References 90 publications

Identification of recombinants of hepatitis B virus genotypes C from Hong Kong China

Identification of recombinants of hepatitis B virus genotypes C from Hong Kong China

Recent Advances in Hepatitis B Treatment

Predicted structure of the hepatitis B virus polymerase reveals an ancient conserved protein fold

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