Jinhong Chang, MD, PhD
Ph: (215) 589- 6325
Areas of Research
Antiviral drug discovery, hepatitis B virus, hepatitis D virus, flaviviruses, and filoviruses
(1991) M.D. Peking University Health Science Center, Beijing, China
(1997) Ph.D. Hepatology Institute, Peking University. Beijing, China
(1998-2001) Postdoctoral Fellow Fox Chase Cancer Center, Philadelphia, PA, U.S.A.
Appointment at the Baruch S. Blumberg Institute: Professor and Director, laboratory of molecular virology and antiviral research, Department of Experimental Therapeutics
Adjunct Associate Professor, Department of Microbiology and Immunology, Drexel University College of Medicine (http://www.drexel.edu/medicine/Faculty/Profiles/Jinhong-Chang/)
Editor, Antiviral Research (https://www.journals.elsevier.com/antiviral-research/editorial-board/jinhong-chang)
Secretory, International Society for Antiviral Research (ISAR) (https://www.isar-icar.com/The-Society)
Discovery and development of antiviral drugs and innate immune modulators for treatment of hepatitis B, hepatitis D, dengue, yellow fever, and other viral hemorrhagic fever.
Zhao Gao, Ph.D., Postdoctoral Research fellow
Julia Ma, M.S. Scientific technician
Lin Zhang, M.S. Scientific technician
Preclinical development and characterization of the mode-of-action of a small molecule yellow fever virus NS4B inhibitor
In a high throughput screening campaign, we discovered a benzodiazepine compound BDAA that potently inhibited yellow fever virus (YFV) replication in vitro and in an YFV infected hamster model. Chemical genetic studies have revealed a novel mechanism of BDAA against YFV. We have demonstrated that BDAA’s interaction with NS4B protein impairs the integrity of YFV replication complex, which inhibits viral RNA replication and promotes viral RNA releasing from replication complex and consequentially activates RIG-I and MDA5. Currently we are using BDAA as a chemical probe to examine the molecular details of NS4B’s dual function in viral RNA replication and evasion of host cellular innate immune response and understand how these processes are simultaneously disrupted by small molecule compound. Lead optimization is currently ongoing to further improve the druggable properties and in vivo efficacy of BDAA.
Discovery and development of human STING agonists for treatment of chronic hepatitis B
Stimulator of interferon genes (STING) is the adaptor protein of multiple cytoplasmic DNA receptors. Cytoplasmic DNA activates cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) to produce cGAMP, which subsequently binds to STING and induces IFNs and other cytokines. previously, we showed that 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a small molecule mouse STING agonist, induced a type I-IFN dominant cytokine response in macrophages, which potently suppressed HBV replication in mouse hepatocytes by reducing the amount of cytoplasmic viral nucleocapsids. Moreover, intraperitoneal administration of DMXAA significantly induced the expression of IFN-stimulated genes and reduced HBV DNA replication intermediates in the livers of HBV hydrodynamically injected mice. Our study thus proves the concept that activation of STING pathway induces a potent innate antiviral immune response against HBV, and the development of small molecular human STING agonists as immunotherapeutic agents for treatment of chronic hepatitis B is warranted. Recently, we developed a cell-based high throughput screening assay and identified several small molecule human STING agonists. Characterization of their effect on viral infection, mode of action as well as structure-activity-relationship studies are currently under way.
Host-targeting antiviral drug development: Iminosugar ER α-glucosidase inhibitors
Almost all the antiviral drugs approved by US FDA for treatment of viral diseases inhibit virus-encoded enzymes or disrupt the interaction between viral and host cellular proteins. However, targeting host functions essential for viral replication has been considered as a potential broad-spectrum and resistance-refractory therapeutic approach. These host function-targeted broad-spectrum antiviral agents do not rely on time-consuming etiologic diagnosis and thus should be particularly valuable in management of viral hemorrhagic fever and respiratory tract viral infections, the medical conditions that can be caused by many different enveloped RNA viruses and with short window for medical intervention.
Interestingly, despite that many inhibitors of host functions have been demonstrated to inhibit a specific virus or a broad-spectrum of viruses in cultured cells, the in vivo antiviral efficacy has only been demonstrated for the inhibitors of a few host cellular components. Endoplasmic reticulum (ER)-resident α-glucosidase I and II sequentially trim the three terminal glucose moieties on the N-linked glycans attached to the nascent glycoproteins. These reactions are the first steps of N-linked glycan processing and are essential for proper folding and function of many glycoproteins. Because most of the viral envelope glycoproteins contain N-linked glycans, inhibition of ER α-glucosidases with derivatives of 1-deoxynojirimycin (DNJ) or castanospermine (CAST), the two well-studied pharmacophores of α-glucosidase inhibitors, efficiently disrupts the morphogenesis of a broad-spectrum of enveloped viruses. During the last several years, through extensive lead optimization efforts, we identified DNJ derivatives (iminosugars) with improved antiviral activity and reduced toxicity and have already demonstrated that several iminosugars efficiently suppressed the replication of dengue virus in mice and improved the survival rates of mice infected by dengue virus, Ebolavirus and Marberg virus. To further improve the in vivo antiviral efficacy and reduce the intestine stress and diarrhea due to nonselectively inhibition of gut glucosidases by the iminosugars, we are currently developing iminosugar prodrugs with improved bioavailability and metabolic activation in blood and targeted tissues for treatment of viral hemorrhagic fever and influenza A.
The research in Dr. Chang’s laboratory is mainly focused on discovery and development of direct-acting or host-targeting antivirals and innate immune modulators for treatment of chronic hepatitis B and D, as well as several acute viral diseases, such as yellow fever and other viral hemorrhagic fever. Three classes of antiviral and innate immune modulators are currently under preclinical development.
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