Sulfamoylbenzamide Derivatives Inhibit the Assembly of Hepatitis B Virus Nucleocapsids
Open Access
- 15 June 2013
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 87 (12), 6931-6942
- https://doi.org/10.1128/jvi.00582-13
Abstract
Chronic hepatitis B virus (HBV) infection, a serious public health problem leading to cirrhosis and hepatocellular carcinoma, is currently treated with either pegylated alpha interferon (pegIFN-α) or one of the five nucleos(t)ide analogue viral DNA polymerase inhibitors. However, neither pegIFN-α nor nucleos(t)ide analogues are capable of reliably curing the viral infection. In order to develop novel antiviral drugs against HBV, we established a cell-based screening assay by using an immortalized mouse hepatocyte-derived stable cell line supporting a high level of HBV replication in a tetracycline-inducible manner. Screening of a library consisting of 26,900 small molecules led to the discovery of a series of sulfamoylbenzamide (SBA) derivatives that significantly reduced the amount of cytoplasmic HBV DNA. Structure-activity relationship studies have thus far identified a group of fluorine-substituted SBAs with submicromolar antiviral activity against HBV in human hepatoma cells. Mechanistic analyses reveal that the compounds dose dependently inhibit the formation of pregenomic RNA (pgRNA)-containing nucleocapsids of HBV but not other animal hepadnaviruses, such as woodchuck hepatitis virus (WHV) and duck hepatitis B virus (DHBV). Moreover, heterologous genetic complementation studies of capsid protein, DNA polymerase, and pgRNA between HBV and WHV suggest that HBV capsid protein confers sensitivity to the SBAs. In summary, SBAs represent a novel chemical entity with superior activity and a unique antiviral mechanism and are thus warranted for further development as novel antiviral therapeutics for the treatment of chronic hepatitis B.Keywords
This publication has 63 references indexed in Scilit:
- Identification of Disubstituted Sulfonamide Compounds as Specific Inhibitors of Hepatitis B Virus Covalently Closed Circular DNA FormationAntimicrobial Agents and Chemotherapy, 2012
- In Vitro Epsilon RNA-Dependent Protein Priming Activity of Human Hepatitis B Virus PolymeraseJournal of Virology, 2012
- Design, Synthesis, and Biological Evaluation of Triazolo-pyrimidine Derivatives as Novel Inhibitors of Hepatitis B Virus Surface Antigen (HBsAg) SecretionJournal of Medicinal Chemistry, 2011
- Serine Phosphoacceptor Sites within the Core Protein of Hepatitis B Virus Contribute to Genome Replication PleiotropicallyPLOS ONE, 2011
- The Arginine Clusters of the Carboxy-Terminal Domain of the Core Protein of Hepatitis B Virus Make Pleiotropic Contributions to Genome ReplicationJournal of Virology, 2011
- Indoleamine 2,3-Dioxygenase Mediates the Antiviral Effect of Gamma Interferon against Hepatitis B Virus in Human Hepatocyte-Derived CellsJournal of Virology, 2011
- Trapping of Hepatitis B Virus Capsid Assembly Intermediates by Phenylpropenamide Assembly AcceleratorsACS Chemical Biology, 2010
- Interferons Accelerate Decay of Replication-Competent Nucleocapsids of Hepatitis B VirusJournal of Virology, 2010
- A Substituted Tetrahydro-Tetrazolo-Pyrimidine Is a Specific and Novel Inhibitor of Hepatitis B Virus Surface Antigen SecretionAntimicrobial Agents and Chemotherapy, 2007
- Characterization of the Intracellular Deproteinized Relaxed Circular DNA of Hepatitis B Virus: an Intermediate of Covalently Closed Circular DNA FormationJournal of Virology, 2007