My laboratory has two major projects: (1) the development of small molecule antivirals and (2) discovery of innate immune modulators with therapeutic potential.
(1) Development of antivirals, with focus on flaviviruses such as hepatitis C virus and dengue virus as well as other hemorrhagic fever viruses.
Imino sugars are broad-spectrum antiviral agents that inhibit glucosidases (enzymes that are required for morphogenesis of many enveloped viruses) and modulate host antiviral responses. Our lead compound, NNDNJ has been shown to have some extent of efficacy in animal models of flavivirus infection. The overall goal of this project is to discover compounds that are superior to NNDNJ, through rational chemical modification on NNDNJ, and develop into orally available imino sugar for the treatment of flaviviruses and other hemorrhagic fever virus infections.
Currently, we have performed significant structure-activity-relationship studies, through rational designed chemical modifications. Several leads have been identified with in vivo animal efficacy against dengue virus, ebola virus and Marburg virus. Advanced pre-clinical studies are undergoing to optimize in vivo treatment protocol, and thoroughly analyze the toxicology profile of the leads.
(2) Discovery of antivirals through modulation of the innate immune response.
Novel high throughput screening systems have been established to screen >26,000 in house libraries, and identify small molecule compounds that can differentially regulate interferon production and the induction of inflammatory cytokines. To this end, we have identified several small molecule compounds that specifically enhance induction of type I interferon and with antiviral potentials. The antiviral activities of these compounds have been obtained with multiple human viruses, including hepatitis B virus (HBV). The detailed molecular targets for these compounds are currently under investigation.
Selected Research Publications:
"RO 90-7501 enhances TLR3 and RLR agonist induced antiviral response"
Guo F, Mead J, Aliya N, Cuconati A, Wei L, Li K, Block TM, Guo JT, and J Chang
PLoS ONE, 7:e42583, 2012.
Design, Synthesis, and Biological Evaluation of N-Alkylated Deoxynojirimycin (DNJ) Derivatives for the Treatment of Dengue Virus Infection.
Yu W, Gill T, Wang L, Du Y, Ye H, Qu X, Guo JT, Cuconati A, Zhao K, Block TM, Xu X. and J Chang
J. Med. Chem., 55: 6061-6075, 2012.
"Competitive inhibitor of cellular alpha-glucosidases protects mice from lethal dengue virus infection"
Chang J, Schul W, Yip A, Xu X, Guo JT, and TM Block
Antiviral Res., 92: 369-371, 2011.
"Inhibitors of endoplasmic reticulum alpha-glucosidaes potently suppress hepatitis C virus virion assembly and release"
Qu X, Pan X, Weidner J, Yu W, Alonzi D, Xu X, Butters T, Block TM, Guo JT, and Chang J
Antimicrobial Agents and Chemotherapy, 55: 1036-1044, 2011.
"Combination of a-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo"
Chang J, 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, Shi P-Y, Guo J-T and Block T
Antiviral Research, 89: 26-34, 2011.
"Novel Imino Sugar Derivatives Demonstrate Potent Antiviral Activity against Flaviviruses"
Chang J, Wang L, Ma D, Qu X, Guo H, Xu X, Mason PM, Bourne N, Moriarty R, Gu B, Guo JT, and Block TM.
Antimicrobial Agents and Chemotherapy, 53(4): 1501-1508, 2009.
"Liver specific microRNA, miR-122, enhances the replication of hepatitis C virus in non-hepatic cells"
Chang J, Guo JT, Jiang D, Guo H, Taylor J, and Block TM
The Journal of Virology, 82: 8215-8223, 2008
"Transcription of hepatitis delta virus RNA by RNA polymerase II"
Chang J, Nie X, Chang HE, Han Z, and Taylor J
The Journal of Virology, 82: 1118-1127, 2008.
"Assembly of hepatitis B virus envelope proteins onto a lentivirus pseudotype that infects primary human hepatocytes"
Chai N. Chang HE, Nicolas E, Gudima S, Chang J, and Taylor J
The Journal of Virology, 81: 10897-10904, 2007.
"Immunoadhesins containing pre-S domains of hepatitis B virus large envelope protein are secreted and inhibit virus infection"
Chai N, Gudima S, Chang J, and Taylor J.
The Journal of Virology, 81: 4912-8, 2007
"Action of inhibitors on accumulation of processed hepatitis delta virus RNA"
Chang J, Nie X, Gudima S, and Taylor J
The Journal of Virology, 80: 3205-3214, 2006.
"Development of a novel system to study hepatitis delta virus genome replication"
Chang J, Gudima S, Tarn C, Nie X, and Taylor J
The Journal of Virology, 79: 8182-8188, 2005.
"Evolution of hepatitis delta virus RNA genome following long-term replication in cell culture"
Chang J, Gudima S, and Taylor J
The Journal of Virology, 79: 13310-13316, 2005.
"Resistance of human hepatitis delta virus RNAs to dicer activity"
Chang J, Provost P, and Taylor J
The Journal of Virology, 77: 11910-11917, 2003.
"Susceptibility of human hepatitis delta virus RNAs to small interfering RNA action"
Chang J and Taylor J
The Journal of Virology, 77: 9728-9731, 2003.
"In vivo RNA-directed transcription, with template switching, by a mammalian RNA polymerase"
Chang J and Taylor J
The EMBO Journal, 21: 1-8, 2002.
"Replication of the genome of human hepatitis delta virus is initiated in mouse hepatocytes following intravenous injection of naked DNA or RNA sequences"
Chang J, Sigal L, Lerro A, and Taylor J
The Journal of Virology, 75: 3469-3473, 2001.