Drexel University

Baruch S. Blumberg Institute

Fox Chase Cancer Center

Arbutus Biopharma Corporation

Ju-Tao Guo

Timothy Michael Block

Jinhong Chang

Xiaodong Xu

William Alvin Kinney

Harold R Almond

Andrea Cuconati

Fang Guo

Hong Ye

Tong Xiao

Yanming Du

Huagang Lu

Haitao Guo

Simon David Peter Baugh

Christoph Seeger

Dawei Cai

Qing Zhu

Simon David Baugh

The present invention provides small molecule inhibitors of hepatitis B virus (HBV) covalently closed circular (ccc) DNA, which are useful as therapeutics in the management of chronic HBV. The compounds of the invention achieve epigenetic modification of the cccDNA, histone modification and histone deacetylase activity inhibition, thus modulating HBV cccDNA. The present invention further provides methods for modulating HBV cccDNA, for treating or preventing HBV in a subject, and for modulating cccDNA transcription of hepatitis B in a subject.

Modulation of hepatitis B virus cccDNA transcription

Provided herein are methods of treating a subject having hepatitis B viral (HBV) infection. More specifically, disclosed herein are methods of stimulating the innate cytokine response in macrophages, dendritic cells and/or liver non-parenchymal cells with small molecular agonists of STING to suppress HBV replication in hepatocytes. The methods are especially suitable for use in the treatment of chronic HBV infections. Also disclosed herein are methods of identifying compounds useful in the treatment of HBV infection.

Use of sting agonists to treat chronic hepatitis B virus infection

The present invention provides novel compounds of formula (I) and methods of use thereof. In certain embodiments, the compounds of the invention are useful as nucleocapsid assembly inhibitors. In other embodiments, the compounds of the invention are useful as pregenomic RNA encapsidation inhibitors of Hepatitis B virus (HBV). In yet other embodiments, the compounds of the invention are useful for the treatment of viral infection, including HBV and related viral infections.

Antiviral agents against HBV infection

The present invention provides sulfamoylbenzamide derivatives, and pharmaceutical compositions thereof. In certain embodiments, the compounds and pharmaceutical compositions of the invention inhibit pregenomic RNA encapsidation. In other embodiments, the compounds and pharmaceutical compositions of the invention are useful for treating Hepatitis B virus (HBV) infection.

Sulfamoylbenzamide derivatives as antiviral agents against HBV infection

Pharmaceutical compositions of the invention comprise covalently closed circular DNA formation inhibitors having a disease-modifying action in the treatment of diseases associated with the formation of covalently closed circular DNA that include hepatitis B infection, and any disease involving formation of covalently closed circular DNA.

Inhibitors of hepatitis B virus covalently closed circular DNA formation and their method of use

The invention includes methods of treating a subject having hepatitis B viral (HBV) infection. In certain embodiments, the method of the invention comprises stimulating the innate cytokine response in macrophages, dendritic cells and/or liver non-parenchymal cells with small molecular STING agonists, thus suppressing HBV replication in hepatocytes. In other embodiments, the method of the invention can be used to treat chronic HBV infections. The invention further provides methods of identifying compounds useful in treating HBV infection in a subject.

Use of sting agonists to treat hepatitis B virus infection

Modulation of hepatitis B virus CCCDNA transcription

Pharmaceutical compositions of the invention comprise sulfamoylbenzamide derivative useful as pregenomic RNA encapsidation inhibitors, useful for the treatment of Hepatitis B virus (HBV) infection.

The present invention describes a unique antiviral screen system. The assay is based on quantitatively monitoring viral activation of host cell beta-interferon (IFN-&#x3b2;) gene expression in a HEK293-derived reporter cell line expressing a firefly luciferase gene under the control of a human IFN-&#x3b2; promoter. Unlike the traditional high throughput antiviral assays that measure either the reduction of viral components/yields or cytopathic effect, the readout of the reporter assay in the present invention is the virus-induced host cellular innate immune response. Hence, the assay allows for identification of compounds that inhibit virus infection. In addition, because induction of IFN is one of the most common attributes of viruses, the assay is applicable to all the viruses that are able to infect the reporter cell line and induce IFN-&#x3b2; expression. Compounds that interfere with viral mediated activation of the interferon pathway in a primary screen, can be further screened with virus-specific assay to confirm their antiviral activity.

Benzodiazepine compounds with anti-flavivirus activity

Cells and cell lines which replicate HCV of non-hepatic human and non human origin are disclosed. Also provided are methods of using such cells and cell lines to identify anti-HCV agents for the treatment of HCV infection.

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Lansdale, PA, United States of America

Ju-Tao Guo