A novel orally available small molecule that inhibits hepatitis B virus expression

Mueller, Henrik; Wildum, Steffen; Luangsay, Souphalone; Walther, Johanna; Lopez, Anaïs; Tropberger, Philipp; Ottaviani, Giorgio; Lu, Wenzhe; Parrott, Neil; Zhang, Jitao David; Schmucki, Roland; Raček, Tomáš; Hoflack, Jean-Christophe; Kueng, Erich; Point, Floriane; Zhou, Xue; Steiner, Guido; Lütgehetmann, Marc; Rapp, Gianna; Volz, Tassilo; Dandri, Maura; Song, Yang; Young, John A. T.; Javanbakht, Hassan

doi:10.1016/j.jhep.2017.10.014

Cited by 119 publications

(130 citation statements)

References 37 publications

(43 reference statements)

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“…Differentiated HepaRG hepatoma (dHepaRG) and dHepaRG asialoglycoprotein receptor 1/2 (ASGPR1/2) cell lines were infected by HBV genotype D as described . Primary human hepatocytes (PHHs) isolated by the collagenase perfusion method from chimeric urokinase‐type plasminogen activator/severe combined immunodeficiency (uPA/SCID) mice with humanized livers were obtained from PhoenixBio (Hiroshima, Japan).…”

Section: Methodsmentioning

confidence: 99%

PAPD5/7 Are Host Factors That Are Required for Hepatitis B Virus RNA Stabilization

et al. 2019

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RG7834 is a potent, orally bioavailable small‐molecule inhibitor of hepatitis B virus (HBV) gene expression that belongs to the dihydroquinolizinone (DHQ) chemical class and uniquely blocks production of both viral DNA and antigens. In this study, we used DHQ compounds as tools in a compound‐based adaptation version of the yeast three‐hybrid screen to identify the cognate cellular protein targets, the non‐canonical poly(A) RNA polymerase associated domain containing proteins 5 and 7 (PAPD5 and PAPD7). Interaction with RG7834 was mapped to the catalytic domains of the two cellular enzymes. The role of PAPD5 and PAPD7 in HBV replication was confirmed by oligonucleotide‐mediated knockdown studies that phenocopied the result seen with RG7834‐treated HBV‐infected hepatocytes. The greatest effect on HBV gene expression was seen when PAPD5 and PAPD7 mRNAs were simultaneously knocked down, suggesting that the two cellular proteins play a redundant role in maintaining HBV mRNA levels. In addition, as seen previously with RG7834 treatment, PAPD5 and PAPD7 knockdown led to destabilization and degradation of HBV mRNA without impacting production of viral RNA transcripts. Conclusion: We identify PAPD5 and PAPD7 as cellular host factors required for HBV RNA stabilization and as therapeutic targets for the HBV cure.

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Section: Methodsmentioning

confidence: 99%

PAPD5/7 Are Host Factors That Are Required for Hepatitis B Virus RNA Stabilization

et al. 2019

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“…However, these trials were recently terminated because of formulation toxicities . Interestingly, a recent study has identified a novel small molecule inhibitor that can reduce viral messenger RNA (mRNA) and pgRNA expression . Despite strong evidence that RG7834 does not function in as RNAi, it is not yet clear how this therapeutic agent can suppress HBV transcription in a virus‐specific manner.…”

Section: Novel Therapeutic Strategies In Developmentmentioning

confidence: 99%

Towards HBV curative therapies

Schinazi

Ehteshami

Bassit

et al. 2018

Liver International

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Tremendous progress has been made over the last 2 decades to discover and develop approaches to control hepatitis B virus (HBV) infections and to prevent the development of hepatocellular carcinoma using various interferons and small molecules as antiviral agents. However, none of these agents have significant impact on eliminating HBV from infected cells. Currently the emphasis is on silencing or eliminating cccDNA, which could lead to a cure for HBV. Various approaches are being developed including the development of capsid effectors, CRISPR/Cas9, TALENS, siRNA, entry and secretion inhibitors, as well as immunological approaches. It is very likely that a combination of these modalities will need to be employed to successfully eliminate HBV or prevent virus rebound on discontinuation of therapy. In the next 5 years clinical data will emerge which will provide insight on the safety and feasibility of these approaches and if they can be applied to eradicate HBV infections globally. In this review, we summarize current treatments and we highlight and examine recent therapeutic strategies that are currently being evaluated at the preclinical and clinical stage. K E Y W O R D Santiviral agents, cccDNA, HBV cure, immunotherapy

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“…They are likely to interact with host functions that mediate these processes, and given how unusual are their structures (found more often in noncoding than in coding RNAs), they may present opportunities for antiviral targeting. Curiously, there is evidence that HBV pregenomic RNA may use the host TRAMP pathway normally used for quality control and degradation of defective host transcripts, for its maturation (Javanbakht et al, 2017; Mueller et al, 2018; Zhou et al, 2018). …”

Section: Transcription Of Cccdna and Transport Of Rna Out Of The Nucleusmentioning

confidence: 99%

“…Recently, we and others have reported that a small molecule, a dihydroxyquinoline, can cause the rapid degradation of HBV transcripts (Mueller et al, 2018; Zhou et al, 2018). The degradation occurs in the nucleus, and is selective, to the extent that most other host transcripts and proteins tested are not significantly affected, over the period of study.…”

Section: Transcription Of Cccdna and Transport Of Rna Out Of The Nucleusmentioning

confidence: 99%

Host functions used by hepatitis B virus to complete its life cycle: Implications for developing host-targeting agents to treat chronic hepatitis B

et al. 2018

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Similar to other mammalian viruses, the life cycle of hepatitis B virus (HBV) is heavily dependent upon and regulated by cellular (host) functions. These cellular functions can be generally placed in to two categories: (a) intrinsic host restriction factors and innate defenses, which must be evaded or repressed by the virus; and (b) gene products that provide functions necessary for the virus to complete its life cycle. Some of these functions may apply to all viruses, but some may be specific to HBV. In certain cases, the virus may depend upon the host function much more than does the host itself. Knowing which host functions regulate the different steps of a virus’ life cycle, can lead to new antiviral targets and help in developing novel treatment strategies, in addition to improving a fundamental understanding of viral pathogenesis. Therefore, in this review we will discuss known host factors which influence key steps of HBV life cycle, and further elucidate therapeutic interventions targeting host-HBV interactions.

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A novel orally available small molecule that inhibits hepatitis B virus expression

Cited by 119 publications

References 37 publications

PAPD5/7 Are Host Factors That Are Required for Hepatitis B Virus RNA Stabilization

PAPD5/7 Are Host Factors That Are Required for Hepatitis B Virus RNA Stabilization

Towards HBV curative therapies

Host functions used by hepatitis B virus to complete its life cycle: Implications for developing host-targeting agents to treat chronic hepatitis B

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