Office 223 / Lab 231
PA Biotechnology Center
3805 Old Easton Road
Doylestown, PA 18902
TEL: 215-489-4905
FAX: 215-489-4920
Anand.Mehta@drexelmed.edu
Keywords:
Hepatitis, Anti-virals, Glycobiology, Glycovirology, Protein folding, Protein trafficking, Diagnostic markers, Proteomics.
Research Interests:
Hepatitis B virus (HBV) is the prototypic member of the Hepadnaviridae family of viruses that chronically infect 350 million people worldwide. The major complication is the development of primary hepatocellular carcinoma estimated to cause 500,000 deaths annually. Although there is no cure for HBV infection, several therapeutic options exist. However, the poor response rate and development of resistant mutants highlight the need for alternatives and complements to the conventional therapeutic regimens.
Our laboratory has two major projects: the development of new HBV therapeutics and the search for early markers of liver cancer. In our examination of the role of N-linked glycosylation in HBV morphogenesis, we discovered two classes of anti-HBV agents. The first involved the use of inhibitors of the N-linked glycan processing pathway as anti-viral agents. Our prior work had determined that inhibitors of alpha glucosidases could inhibit HBV and Bovine viral diarrhea virus (BVDV, a tissue culture surrogate for Hepatitis C virus) secretion in vitro and in vivo. In an effort to develop more potent agents, a modified glucosidase inhibitor was developed, N-Nonyl-DNJ, which had a 100 fold greater potency than the parent compound. However, in tissue culture, this anti-viral activity did not correlate with glucosidase inhibition. That is, at doses that were anti-viral, little or no glucosidase inhibition was seen. This lead to the creation of the galactose isomer of N-nonyl-DNJ called N-Nonyl-DGJ. N-nonyl-DGJ is not an inhibitor of the alpha glucosidases but still posses potent anti-HBV activity. In studying the mechanism it appears that N-nonyl-DGJ inhibits HBV secretion by inhibiting virion formation in a manner that is very different from the glucosidase inhibitors. Indeed, these compounds appear to be orally available inducers of the interferon pathway and hence may be valuable as both a HBV/HCV anti-viral as well as an immune modulator.
Our second approach towards the discovery of HBV therapeutics involves the development of immunological agents to complement traditional anti-virals. That is, there is a growing body of evidence that animals and people chronically infected with hepadnaviruses possess the potential to mount a beneficial immunological response to the virus. It appears that this response, in experimental animals and in chronically infected people, can be enhanced or enabled by highly effective and sustained antiviral therapy and vaccination using hepadna viral antigens (Boni et al. Hepatology. 33: 963 2001). Thus, our second approach involves the development of novel HBV DNA vaccines that will be able to generate the appropriate immune response to help cure people of HBV. This work will lead to great insights into the basic biology of protein folding, degradation, antigen presentation and into the development of useful therapeutic products.
In an effort to identify serum biomarkers of HCC, we have developed a targeted glycoproteomic approach. That is, we have utilized a simple quantitative method to identify alterations in glycosylation and subsequently identify the glycoproteins with altered glycosylation, by two-dimensional proteomics (2DE). In the case of primary hepatocellular carcinoma (HCC) we have shown that an increase in the fucosylation of liver derived glycoproteins is associated with the development of cancer. By combining our quantitative glycan sequencing methodology with 2DE we have identified several glycoproteins with altered glycosylation as a function of disease. One such glycoprotein, GP 73, was found to be elevated and hyperfucosylated in animals with HCC. Further analysis of human sera from patients with varying disease states confirmed the specific association of GP73 with the development of HCC. GP 73 is a resident Golgi membrane protein that is know to be upregulated in liver disease including viral infection and, although its function has yet to be elucidated, its expression profile suggests it may serve as a biomarker of liver cancer.
Publications
- Mehta, A., Carrouee, S., Conyers, B., Jordan, R., Butters, T., Dwek, R.A., Block. T.M. Inhibition of Hepatitis B Virus DNA Replication by Imino Sugars without the Inhibition of the DNA Polymease: Therapeutic Implications. Hepatology, 2001 Vol. 33, No. 6, 1488-1495.
- Steel, L.F., T.S. Mattu, A. Mehta, H. Hebestreit, R. Dwek, and T. Block, A proteomics approach for the discovery of early detection markers of hepatocellular carcinoma. Disease Markers, 2001 Vol 17, 179-189
- Ouzounov, S., Mehta,A, Dwek, R.A., Block, T.B., and Jordan, R. “The combination of interferon-?2b and N-butyl Deoxynojirimycin has a greater than additive antiviral effect upon production of infectious bovine viral diarrhea virus (BVDV) in vitro: implications for hepatitis C virus (HCV) therapy”. Antiviral Research. (2002) 55: 425-435.
- Jordan, R., Conyers, B., Wang, L., Mehta,A., Dwek, R.A., Block, T. (2002) “Inhibitors of ER ?-glucosidase I and II reduce infectivity of secreted bovine viral diarrhea virus particles.” Virology 30;295(1):10-9
- Mehta, A., Conyers, B., Tyrrell, D.L.J., Walters, K.A., Graham A. Tipples, G.A., Dwek, R. A., Block, T.M (2002) Structure-activity relationship of a new class of anti-hepatitis B virus agents. Antimicrobial Agents and Chemotherapy, 46(12): p. 4004-4008
- Mehta, A., Ouzounov, S., Jordan, R., Simsek, E., Lu, X., Moriarty, R.M., Jacob, G.,. Dwek, R.A., Block, T.M. (2002) Imino sugars that are less toxic but more potent as antivirals, in vitro, compared to N-n-nonyl DNJ. Antiviral Chemistry and Chemotherapy, 13: 299-304
- Norton PA, Gong Q, Mehta AS, Lu X, Block TM (2003) Hepatitis B virus-mediated changes of apolipoprotein mRNA abundance in cultured hepatoma cells. J Virol. 77(9):5503-6
- Block TM, Mehta AS, Fimmel CJ, Jordan R. (2003) Molecular viral oncology of hepatocellular carcinoma. Oncogene 22(33):5093-6107
- Comunale, M.A., Mattu, T.S., Lowman, M., Evans, A., London, W.T, Block, T.M., Mehta, A. (2004) Identification of Serum Polypeptide Biomarkers for HCC by Proteomics: application of endoglycosidase F in proteomic analysis. Proteomics 2004, 4, 826–838.
- Mehta, A.S., Gu, B., Conyers, B., Ouzounov, S., Wang, L., Romano, P.M., Moriarty, R.M., Dwek, R.M., Block, T.M (2003) Alpha galactosyl ceramide and novel synthetic glycolipids directly induce the innate host defense pathway and have direct anti-viral activity against hepatitis B and C viruses. Antimicrobial Agents and Chemotherapy, 48 (6): 2085–2090.
- Comunale, M.A., Block, Romano, P.M, T.M., Lowman, M., Fimmel, C., Tennant, B.T., Evans, A., London, W.T., Blumberg, B., Dwek, R.A., Mattu, T.S., Mehta, A. (2004) Targeted glycoproteomics identifies a serum glycoprotein that correlates with liver cancer in woodchucks and people, Proc. Natl. Acad. Sci. USA. 102 (3):779–784.
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