Novel Potent Capsid Assembly Modulators Regulate Multiple Steps of the Hepatitis B Virus Life Cycle

Antimicrobial Agents and Chemotherapy
Thomas LahlaliDavid Durantel

Abstract

The assembly of hepatitis B virus (HBV) core protein (HBc) into capsids represents a critical step of viral replication. HBc has multiple functions during the HBV life cycle, which makes it an attractive target for antiviral therapies. Capsid assembly modulators (CAMs) induce the formation of empty capsid or aberrant capsid devoid of pregenomic RNA (pgRNA) and finally block relaxed circular DNA neosynthesis and virion progeny. In this study, the novel CAMs JNJ-827 and JNJ-890 were found to be potent inhibitors of HBV replication with respective half-maximal effective concentrations of 4.7 and 66 nM, respectively, in HepG2.117 cells. Antiviral profiling in differentiated HepaRG (dHepaRG) cells and primary human hepatocytes revealed that these compounds efficiently inhibited HBV replication, as well as de novo establishment of covalently closed circular DNA (cccDNA). In addition to these two known effects of CAMs, we observed for the first time that a CAM, here JNJ-827, when added postinfection for a short-term period, significantly reduced hepatitis B e antigen (HBeAg) secretion without affecting the levels of cccDNA amount, transcription, and hepatitis B surface antigen (HBsAg) secretion. This inhibitory activity resulted from ...Continue Reading

References

Jan 1, 1982·Intervirology·T Michalak, A Nowosławski
Dec 29, 2000·Bioorganic & Medicinal Chemistry Letters·R B PerniR W King
Mar 13, 2001·Journal of Molecular Biology·C T BockH Zentgraf
Nov 15, 2002·Proceedings of the National Academy of Sciences of the United States of America·Philippe GriponChristiane Guguen-Guillouzo
Oct 8, 2004·Proceedings of the National Academy of Sciences of the United States of America·Margaret T ChenDavid R Milich
Jun 2, 2005·Proceedings of the National Academy of Sciences of the United States of America·Stephen J StrayAdam Zlotnick
Sep 30, 2005·Journal of Molecular Recognition : JMR·Adam Zlotnick
Sep 1, 2006·Journal of Virology·Christina R BourneAdam Zlotnick
Sep 29, 2006·Journal of Molecular Recognition : JMR·Stephen J Stray, Adam Zlotnick
Dec 26, 2006·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Kumar VisvanathanStephen Locarnini
Mar 18, 2009·Methods in Enzymology·Sarah Katen, Adam Zlotnick
May 11, 2010·Cold Spring Harbor Perspectives in Biology·Valérie Lallemand-Breitenbach, Hugues de Thé
Jul 21, 2010·Methods in Molecular Biology·Edward L Lecluyse, Eliane Alexandre
Apr 6, 2011·Journal of Molecular Biology·Norman R WattsPaul T Wingfield
May 7, 2011·Epigenetics : Official Journal of the DNA Methylation Society·Yan-Hai GuoZhen Yan
Apr 28, 2012·Gastroenterology·Hashem B El-Serag
Apr 12, 2013·Journal of Virology·Matthew R CampagnaJu-Tao Guo
Mar 12, 2015·Virology·Christoph Seeger, William S Mason
Apr 3, 2015·Cold Spring Harbor Perspectives in Medicine·Fabien Zoulim, David Durantel
Apr 29, 2015·Journal of Hepatology·Stephen LocarniniAnna Lok
Apr 17, 2016·Journal of Hepatology·Marie-Lise BlondotMichael Kann
Apr 27, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Ahmed DiabDavid Durantel

❮ Previous
Next ❯

Citations

Feb 26, 2019·Journal of Viral Hepatitis·Maria G MartinezFabien Zoulim
May 11, 2019·Reviews in Medical Virology·Yongbin WuBao Zhang
Aug 4, 2019·Journal of Virology·Jianming HuAleem Siddiqui
Oct 30, 2019·Antimicrobial Agents and Chemotherapy·Chunkyu KoUlrike Protzer
Nov 13, 2019·Antimicrobial Agents and Chemotherapy·Franck AmblardRaymond F Schinazi
Feb 26, 2020·Antimicrobial Agents and Chemotherapy·Jan Martin BerkeFrederik Pauwels
Aug 24, 2019·Frontiers in Molecular Biosciences·Shishan WangAnja Böckmann
Aug 29, 2019·Nature Reviews. Drug Discovery·Gregory C FanningAntonio Bertoletti
Feb 23, 2020·Liver International : Official Journal of the International Association for the Study of the Liver·Maria G MartinezFabien Zoulim
Sep 2, 2020·Antimicrobial Agents and Chemotherapy·Qi HuangRichard Colonno
Jul 10, 2019·Antiviral Research·Caroline CharreCaroline Scholtès
Dec 12, 2018·ACS Infectious Diseases·Xuexiang ZhangJinhong Chang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Adhesion Molecules in Health and Disease

Cell adhesion molecules are a subset of cell adhesion proteins located on the cell surface involved in binding with other cells or with the extracellular matrix in the process called cell adhesion. In essence, cell adhesion molecules help cells stick to each other and to their surroundings. Cell adhesion is a crucial component in maintaining tissue structure and function. Discover the latest research on adhesion molecule and their role in health and disease here.

CRISPR Screens in Drug Resistance

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on the application of CRISPR-Cas system in high-throughput genome-wide screens to identify genes that may confer drug resistance.