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Identification of a Bifunctional HBV...

Bradley, Daniel P.,

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Identification of a Bifunctional HBV RNaseH-Capsid Inhibitor and Mechanistic Analysis of Cytotoxicity of α-Hydroxytroplone HBV-RNaseH Inhibitors /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Identification of a Bifunctional HBV RNaseH-Capsid Inhibitor and Mechanistic Analysis of Cytotoxicity of α-Hydroxytroplone HBV-RNaseH Inhibitors // Daniel P Bradley.
Author:	Bradley, Daniel P.,
Description:	1 electronic resource (171 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-01, Section: B.
Contained By:	Dissertations Abstracts International86-01B.
Subject:	Virology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31331792
ISBN:	9798383284285

Identification of a Bifunctional HBV RNaseH-Capsid Inhibitor and Mechanistic Analysis of Cytotoxicity of α-Hydroxytroplone HBV-RNaseH Inhibitors /
Bradley, Daniel P.,

Identification of a Bifunctional HBV RNaseH-Capsid Inhibitor and Mechanistic Analysis of Cytotoxicity of α-Hydroxytroplone HBV-RNaseH Inhibitors /Daniel P Bradley. - 1 electronic resource (171 pages)

Source: Dissertations Abstracts International, Volume: 86-01, Section: B.

Heptatits B virus (HBV) is a global pathogen that chronically infects >250 million people. HBV replicates by protein primed reverse transcription by a unique mechanism mediated by the viral polymerase (P) protein. P has evaded structural analysis for decades, despite being the target for antiviral therapies. Using the algorithmic protein folding prediction software AlphaFold2, we generated and validated a three-dimensional model of P, which provided unique insight to the confirmation of the Terminal Protein (TP) and priming of viral replication. The model of P further demonstrated utility for mechanistic analysis and in silico docking of replication inhibitors. Current antiviral therapies include nulceos(t)ide analogs that effectively suppress HBV replication but are not curative, therefore new therapies with unique mechanisms of action are needed to cure HBV. The Tavis lab has developed potent antivirals that target the ribonuclease H (RNaseH) activity of P and block viral replication with nanomolar efficacy. Preclinical analysis and development are ongoing, concurrently we have been evaluating the cellular effects and antiviral activities of HBV RNaseH inhibitors to inform our drug development efforts. Our analysis has identified a reactive oxygen species (ROS) dependent mechanism of cytotoxicity for the alpha-hydroxytropolone class of HBV RNaseH inhibitors, identifying a potential safety concern before in vivo studies. Separately, our evaluation of the antiviral activities of HBV RNaseH inhibitors identified a chemotype of bifunctional compounds that decrease capsid accumulation. HBV capsids are proteinaceous shells that assemble around the pre-genomic RNA (pgRNA), forming nucleocapsids. Capsids also self-assemble into genome-free or 'empty' capsids in excess compared to nucleocapsids. By measuring intracellular capsid accumulation, we identified the N-hydroxypyridinediones (HPD) chemotype of HBV RNaseH inhibitors as possessing novel capsid accumulation modulator (CAM) activities. The representative HPD 1466 inhibited empty capsid accumulation independent of viral replication and inhibited biochemical capsid assembly reactions with purified capsid protein. We conclude that the bimodal HPD HBV RNaseH inhibitor 1466 is the prototypic member of a new class of CAM (CAM-I) that inhibits capsid assembly rather than accelerating it as do all other CAM classes. These results lay the foundation for the identification of novel HBV core protein targeting antivirals.

English

ISBN: 9798383284285Subjects--Topical Terms:

642304
Virology.
Subjects--Index Terms:

Capsid assembly modulator

Identification of a Bifunctional HBV RNaseH-Capsid Inhibitor and Mechanistic Analysis of Cytotoxicity of α-Hydroxytroplone HBV-RNaseH Inhibitors /
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520 $a Heptatits B virus (HBV) is a global pathogen that chronically infects >250 million people. HBV replicates by protein primed reverse transcription by a unique mechanism mediated by the viral polymerase (P) protein. P has evaded structural analysis for decades, despite being the target for antiviral therapies. Using the algorithmic protein folding prediction software AlphaFold2, we generated and validated a three-dimensional model of P, which provided unique insight to the confirmation of the Terminal Protein (TP) and priming of viral replication. The model of P further demonstrated utility for mechanistic analysis and in silico docking of replication inhibitors. Current antiviral therapies include nulceos(t)ide analogs that effectively suppress HBV replication but are not curative, therefore new therapies with unique mechanisms of action are needed to cure HBV. The Tavis lab has developed potent antivirals that target the ribonuclease H (RNaseH) activity of P and block viral replication with nanomolar efficacy. Preclinical analysis and development are ongoing, concurrently we have been evaluating the cellular effects and antiviral activities of HBV RNaseH inhibitors to inform our drug development efforts. Our analysis has identified a reactive oxygen species (ROS) dependent mechanism of cytotoxicity for the alpha-hydroxytropolone class of HBV RNaseH inhibitors, identifying a potential safety concern before in vivo studies. Separately, our evaluation of the antiviral activities of HBV RNaseH inhibitors identified a chemotype of bifunctional compounds that decrease capsid accumulation. HBV capsids are proteinaceous shells that assemble around the pre-genomic RNA (pgRNA), forming nucleocapsids. Capsids also self-assemble into genome-free or 'empty' capsids in excess compared to nucleocapsids. By measuring intracellular capsid accumulation, we identified the N-hydroxypyridinediones (HPD) chemotype of HBV RNaseH inhibitors as possessing novel capsid accumulation modulator (CAM) activities. The representative HPD 1466 inhibited empty capsid accumulation independent of viral replication and inhibited biochemical capsid assembly reactions with purified capsid protein. We conclude that the bimodal HPD HBV RNaseH inhibitor 1466 is the prototypic member of a new class of CAM (CAM-I) that inhibits capsid assembly rather than accelerating it as do all other CAM classes. These results lay the foundation for the identification of novel HBV core protein targeting antivirals.
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653 $a HBV polymerase
653 $a Hepatitis B virus
653 $a RNaseH inhibitor
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