Drexel University

Baruch S. Blumberg Institute

Institute for Hepatitis and Virus Research

Jinhong Chang

Timothy Michael Block

Ju-Tao Guo

Yanming Du

Xiaodong Xu

William Alvin Kinney

Hong Ye

Harold R Almond

Fang Guo

Andrea Cuconati

Pharmaceutical compositions of the invention comprise functionalized benzamide derivatives useful as cyclic GMP-AMP synthase-Stimulator of interferon gene (cGAS-STING) pathway agonists, and useful for treating viral diseases and boost antitumor immunity.

Benzamide derivatives as cGAS-sting pathway agonists

Described herein are alkylated imino sugars derivatives having a disease-modifying action in the treatment of diseases associated with glucosidase activity that include viral hemorrhagic fevers and other enveloped viruses, and any other diseases involving glucosidase activity.

2,3-diacylated, 2- and 3-mono-acylated alkylated imino sugars exhibiting glucosidase inhibition and their method of use

Pharmaceutical compositions of the invention comprise alkylated imino sugars derivatives having a disease-modifying action in the treatment of diseases associated with glucosidase activity that include Viral hemorrhagic fevers, and any other diseases involving glucosidase activity.

Alkylated imino sugars exhibiting glucosidase inhibition and their method of use

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 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

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

Imino sugars, such as deoxynojirimycin (DNJ), are glucose analogues that selectively inhibit cellular &#x3b1;-glucosidase I and II (enzymes that process N-linked glycans in glycoprotein) and exhibit broad spectrum antiviral activities against many enveloped viruses. Previously we have reported a novel DNJ derivative, OSL-95II, with antiviral activity and reduced cytotoxicity. In order to develop imino sugars with more potent antiviral activity as well as improved toxicity profile, OSL-95II was modified by diversifying the nitrogen linked alkylated side chain. The antiviral activities were initially tested in bovine viral diarrhea virus (BVDV) infected MDBK cells, yielding several imino sugar derivatives with novel structure and superior antiviral activity and toxicity profile. Furthermore, these new compounds were shown to be active against Dengue virus (DV) and West Nile virus (WNV) infection in BHK cells where potent anti-DV activity having submicromolar EC50 values and SI of greater than 900. These compounds represent a new generation of iminio sugars and their analogues, having application in the clinical treatment of infection of DV and other members of flaviviridae.

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Chalfont, PA, United States of America

Jinhong Chang