Jinhong Chang, MD, PhD
Blumberg Institute Professor (Principal Investigator)
Ph: (215) 589- 6325
(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
Other appointments: Adjunct Associate Professor, Department of Microbiology and Immunology, Drexel University College of Medicine (http://www.drexel.edu/medicine/Faculty/Profiles/Jinhong-Chang/)
Research interest: Discovery and development of antiviral drugs and innate immune modulators for treatment of hepatitis B, dengue, yellow fever, influenza A, viral hemorrhagic fever
Fang Guo, M.D. Ph.D., Senior Research Associate
Sainan Shu, M.D., Ph.D., Visiting Scientist
Cher Zhang, M.S. Scientific technician
Julia Ma, B.S. Scientific technician
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.
Direct-acting antiviral compounds efficiently suppress yellow fever virus infection
In a high throughput screening campaign for identification of compounds that inhibit the flavivirus-induced IFN-β promoter activation in a 293-derived cell line, we discovered a benzodiazepine compound that potently inhibited yellow fever virus (YFV) replication, modestly inhibited dengue virus infection, but did not inhibit more than twenty other DNA and RNA viruses tested. Preliminary mechanistic studies have now revealed that the compound specifically targets NS4B protein of YFV. Lead optimization and the in vivo antiviral efficacy of the compound and its derivatives are currently under investigation.
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. It was discovered recently that cytoplasmic DNA activates cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) to produce cGAMP, which subsequently binds to STING and induces IFNs and other cytokines. Recently, we showed that 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a 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. Efforts toward discovery of novel small molecular human STING agonists are currently under way.
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 several acute viral diseases, such as influenza A, yellow fever and viral hemorrhagic fever. Three classes of antiviral and innate immune modulators are currently under preclinical development.
Jinhong Chang and Ju-Tao Guo (2015) Treatment of chronic hepatitis B with pattern recognition receptor agonists: Current status and potential for a cure. Antiviral Research. 121:152-159.
Fang Guo, Yanxing Han, Xuesen Zhao, Jianghua Wang, Fei Liu, Chunxiao Xu, Lai Wei, Jian-Dong Jiang, Timothy M. Block, Ju-Tao Guo and Jinhong Chang (2015). STING agonists induce a potent innate antiviral immune response against hepatitis B virus. Antimicrob Agents Chemother. 59(2):1273-81.
Xuesen Zhao, Fang Guo, Mary Ann Comunale, Anand Mehta, Mohit Sehgal, Pooja Jain, Andrea Cuconati, Hanxin Lin, Timothy M. Block, Jinhong Chang and Ju-Tao Guo (2015) Inhibition of ER glucosidases impairs SARS-CoV and HCoV-NL63 spike protein-mediated entry by altering the glycan processing of ACE2. Antimicrob Agents Chemother. 59(1):206-16.
Jinhong Chang, Timothy M. Block and Ju-Tao Guo (2015) Viral resistance of MOGS-CDG patients implies a broad-spectrum strategy against acute virus infections. Antiviral Therapy. 20(3):257-9.
Jinhong Chang, Fang Guo, Xuesen Zhao and Ju-Tao Guo(2014) Therapeutic strategies for a functional cure of chronic hepatitis B virus infection. Acta Pharmaceutica Sinica B. 4(4):248–257 (Highlighted as cover story).
Fang Guo, Xuesen Zhao, Tina Gill, Yan Zhou, Matthew Campagna, Lijuan Wang, Fei Liu, Pinghu Zhang, Laura DiPaolo, Yanming Du, Xiaodong Xu, Dong Jiang, Lai Wei, Andrea Cuconati, Timothy M. Block, Ju-Tao Guo and Jinhong Chang (2014) An interferon-beta promoter reporter assay for high throughput identification of compounds against multiple RNA viruses. Antiviral Res. 107:56-65.
Xuesen Zhao, Fang Guo, Fei Liu, Andrea Cuconati, Jinhong Chang, Timothy M. Block and Ju-Tao Guo. (2014) Interferon induction of IFITM proteins promotes infection by human coronavirus OC43. Proc Natl Acad Sci U S A. 111(18):6756-6761.
Jinhong Chang, Ju-Tao Guo, Yanming Du and Timothy Block (2013). Imino sugar glucosidase inhibitors as broadly active anti-filovirus agents. Emerging Microbes and Infections. e77; doi:10.1038/emi.2013.77.
Fei Liu, Matthew Campagna, Yonghe Qi, Xuesen Zhao, Fang Guo, Chunxiao Xu, Sichen Li, Wenhui Li, Timothy M. Block, Jinhong Chang, and Ju-Tao Guo. (2013) Alpha-Interferon Suppresses Hepadnavirus Transcription by Altering Epigenetic Modification of cccDNA Minichromosomes. PLoS Pathogens, 9(9): e1003613.
Jinhong Chang, Timothy M. Block and Ju-Tao Guo (2013) Host ER alpha-glucosidase-targeted antiviral therapy: Current status and future directions. Antiviral Research, 99(3):251-260.
Yanming Du, Hong Ye, Fang Guo, Lijuan Wang, Tina Gill, Noshena Khan,Andrea Cuconati, Ju-Tao Guo, Timothy M. Block, Jinhong Chang, Xiaodong Xu. (2013) Design and synthesis of N-alkyldeoxynojirimycin derivatives with improved metabolic stability as inhibitors of BVDV and Tacaribe virus. Bioorganic & Medicinal Chemistry Letters. 23(14):4258-62.
Matthew R. Campagna, Fei Liu, Richeng Mao, Courtney Mills, Dawei Cai, Fang Guo, Xuesen Zhao, Hong Ye, Andrea Cuconati, Haitao Guo, Jinhong Chang, Xiaodong Xu, Timothy M. Block and Ju-Tao Guo (2013) Sulfamoylbenzamide Derivatives Inhibit the Assembly of Hepatitis B Virus Nucleocapsids. J. Virol. 87(12):6931-42.
Jinhong Chang, Travis K. Warren, Xuesen Zhao, Tina Gill, Lijuan Wang, Mary Ann Comunale, Yanming Du, Wenquan Yu, Hong Ye, Fang Guo, Fei Liu, Ju-Tao Guo, Anand Mehta, Andrea Cuconati, Terry Butters, Sina Bavari, Xiaodong Xu, Timothy M. Block (2013) Small molecule inhibitors of ER α-glucosidases are active against multiple hemorrhagic fever viruses. Antiviral Research. 2013 98(3):432-40.
Yanming Du, Hong Ye, Tina Gill, Lijuan Wang, Fang Guo, Andrea Cuconati, Ju-Tao Guo, Timothy M. Block, Jinhong Chang, Xiaodong Xu. (2013) N-Alkyldeoxynojirimycin derivatives with novel terminal tertiary amide substitution for treatment of bovine viral diarrhea virus (BVDV), Dengue, and Tarcaribe virus infections. Bioorganic & Medicinal Chemistry Letters. 23(7):2172-6.
Jinhong Chang, Timothy Block, Ju-Tao Guo. (2012) The innate immune response to hepatitis B virus infection: Implications for viral pathogenesis and development of therapeutics. Antiviral Research. 96(3):405-413.
Chamoun AM, Chockalingam K, Bobardt M, Simeon R, Jinhong Chang, Gallay P, and Chen Z. (2012) PD404, 182 is a virucidual small molecule that disrupts hepatitis C virus and human immunodeficiency virus. Antimicrobial Agents Chemotherapy. 56(2): 672-81.
Yu W, Gill T, Wang L, Du Y, Ye H, Qu X, Guo JT, Cuconati A, Zhao K, Block TM, Xu X, Jinhong Chang. (2012) Design, Synthesis, and Biological Evaluation of N-Alkylated Deoxynojirimycin (DNJ) Derivatives for the Treatment of Dengue Virus Infection. Journal of Medicinal Chemistry. 55 (3):6061-75.
Fang Guo, Jenifer Mead, Aliya N, Cuconati A, Wei L, Li K, Block TM, Guo JT, Jinhong Chang. (2012) RO 90-7501 enhances TLR3 and RLR agonist induced antiviral response. PLoS ONE. 7(10)e42583,
Timothy Block, Jinhong Chang, and Ju-Tao Guo. (2011) Overview of hepatitis viruses and cancer. Tumor viruses. Edited by E. Denderson.
Jinhong Chang, Schul W, Butters T, Yip A, Liu B, Alonzi D, Reinkensmeier G, Pan X, Qu X, Weidner J, Wang L, Yu W, Borune N, Moriarty R, Xu X, ShiP-Y, Guo J-T and Block T. (2011) Combination of a-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo. Antiviral Research. 89(1):26-34.
Guo H, Pan X, Mao R, Zhang X, Wang L, Lu X, Jinhong Chang, Guo JT, Passic S, Krebs FC, Wigdahl B, Warren TK, Retterer CJ, Bavari S, Xu X, Cuconati A, Block TM. (2011) Alkylated porphyrins have broad antiviral activity against hepadnaviruses, falviviruses, filoviruses, and arenaviruses. Antimicrobial Agents Chemotherapy. 55(2):478-86.
Qu X, Pan X, Weidner J, Yu W, Alonzi D, Xu X, Butters T, Block TM, Guo JT, Jinhong Chang. (2011) Inhibitors of endoplasmic reticulum alpha-glucosidaes potently suppress hepatitis C virus virion assembly and release. Antimicrobial Agents Chemotherapy. 55(3):1036-44.
Jinhong Chang, Schul W, Yip A, Xu X, Guo JT, Block TM. (2011) Competitive inhibitor of cellular alpha-glucosidases protects mice from lethal dengue virus infection. Antiviral Research. 92(2):369-71.