Antiviral agents, Bovine viral diarrhea virus, West nile virus, Hepatitis C virus, replicon, viral pathogenesis, Host-cell interaction, siRNA and gene silencing

The main interest of my laboratory is the discovery and development of small molecule antivirals against Hepatitis C Virus, Bovine Viral Diarrhea Virus and the bioterror agent, West Nile Virus.  In particular, we are actively investigating and developing a group of broad-spectrum antiviral iminosugar compounds that act upon the cellular glycosidase and hence viral glycoprotein processing pathways. In addition to maximizing the potency and minimizing the toxicity of these compounds, we are also investigating further their mechanism of action both in tissue culture and in animal models. We recently started a High Through put effort using West Nile Virus replicon cells to screen for novel small molecule antivirals inhibiting the viral RNA replication as well as boosting host cell innate immune system.  The hits from the screen will be triaged by their activity, specificity, toxicity, mode of action and chemical developability, etc.  We are also studying the host antiviral mechanism for both HCV and West Nile Virus and are searching for molecules that can modulate the interferon pathway in another HTS assay.  Finally, siRNA as therapeutics against Hepatitis C Virus are being explored in the lab. We are searching for siRNAs targeting the conserved sequences of the HCV genome in the HCV replicon system. Potential siRNAs will be further developed with the biotechnology company, Nucleonics, Inc.

1. Gu, B., Rivera-Gonzalez, R., Smith, C.A., and N.A. DeLuca.   Herpes simplex virus infected cell polypeptide 4 preferentially represses Sp1-activated over basal transcription from its own promoter.  Proc. Natl. Acad. Sci. (USA), 90: 9525-9532, 1993.

2. Gu, B., and N.A. DeLuca.  Requirements for activation of the Herpes Simplex Virus glycoprotein C promoter in vitro by the viral regulatory protein ICP4.  J. Virol., 68: 7953-7965, 1994.

3. Rivera-Gonzalez, R., Imbalzano, A.N., Gu, B., and N.A. DeLuca.  The role of ICP4 repressor activity in temporal expression of the IE-3 and latency-associated transcript promoter during HSV-1 infection.  Virology,  202: 550-564, 1994.

4. Gu, B., Kuddus, R., and N.A. DeLuca.  Repression of activator-mediated transcription by herpes simplex virus ICP4 via a mechanism involving interactions with the basal transcription factors TATA-binding protein and TFIIB.  Mol. Cell. Biol., 15: 3618-3626, 1995.

5. Kuddus, R., Gu, B., and N.A. DeLuca.  Relationship between TATA binding protein and Herpes simplex virus type 1 ICP4 DNA binding sites in complex formation and repression of transcription.  J. Virol., 69: 5568-5575, 1995.

6. Cook, W.J., Gu, B., Deluca, N.A., Moynihan, E.B., and D.M. Coen.  Induction of transcription by a viral regulatory protein depends on the relative strengths of functional TATA boxes.  Mol. Cell. Biol., 15: 4998-5006, 1995

7. Sojda, J. 3rd, Gu, B., Lee, J., Hoover, T.R., and B.T. Nixon.  A rhizobial homolog of IHF stimulates transcription of dctA in Rhizobium leguminosarum but not in Sinorhizobium meliloti.  Gene, 238(2): 489-500, 1999.

8. Gu, B., Liu, C., Lin-Goerke, J., Maley, D.R., Gutshell, L.L., Feltenberger, C.A., and A.M. Del Vecchio.  The RNA helicase and nucleotide triphosphatase activities of the bovine viral diarrhea virus NS3 protein are essential for viral replication.   J. Virol.,  74: 1794-1800, 2000.

9. Dhanak, D., Duffy, K.J., Johnston, V., Lin-Goerke, J., Darcy, M., Shaw, A.N., Gu, B., Silverman, C., Gates, A., Nonnemacher, M., Earnshaw, D., Casper, D., Kaura, A., Baker, A., Greenwood, C., Gutshall, L., Maley, D., DelVecchio, A., Macarron, R., Hofmann, G., Alnoah, Z., Cheng, H., Chan, G., Khandekar, S., Keenan, R., and R. Sarisky.  Identification and biological characterization of heterocyclic inhibitors of the hepatitis C virus RNA-dependent RNA polymerase.  J. Biol. Chem., 277: 38322-38327, 2002.

10. Gu, B., Gates, A.T., and R.T. Sarisky.  Replication studies using a genotype 1a subgenomic HCV replicon.  J. Virol., 77: 5352-5359, 2003.

11. Gu, B., Ranjith-Kumar, C.T., Gutshall, L., Johnston, V., Darcy, M.G., Tedesco, R., Duffy, K.J., Gontarek, R., Kao, C.C. and R.T. Sarisky.  Mechanism of action for heterocyclic inhibitors of the Hepatitis C virus RNA-dependent RNA polymerase.   J. Biol. Chem.,  278: 16602-7, 2003.

12. Ranjith-Kumar, C.T., Santos, J.L., Gutshall, L.L., Johnston, V.K., Lin-Goerke, J., Kim, M.J., Porter, D.J., Maley, D., Greenwood, C., Earnshaw, D.L., Baker, A., Gu, B., Silverman, C., Sarisky, R.T., and C. Kao.  Distinct enzymatic profile between the GB virus-B and Hepatitis C virus-encoded RNA-dependent RNA polymerases.  Virology, 312: 270-80, 2003.

13. Nguyen, T.T., Gates, A.T., Gutshall, L.L., Johnston, V.K., Gu, B., Duffy, K.J., and R.T. Sarisky. Resistance profile of an HCV RNA-dependent RNA polymerase Benzothiadiazine inhibitor.  Antimicrob. Agents Chemother., 47: 3525-30, 2003.

14. Frick, D. Rypma, R., Lam, A., and B. Gu.  The NS3 protease/helicase requires an intact protease domain to efficiently unwind duplex RNA.  J. Biol. Chem., 279: 1269-1280, 2004.

15. Xu, H., Gu, B., Nixon, B.T., and T.R. Hoover. Purification and characterization of the AAA+ domain of Sinorhizobium meliloti DctD, a sigma54-dependent transcriptional activator.  J. Bacteriol., 186: 3499-507, 2004.

16. Gates, A.T., Sarisky, R.T., and B. Gu.  Sequence requirements for the development of a chimeric HCV replicon system.  Virus Res., 100: 213-222, 2004.

17. Gu, B., Gutshall, L.L., Maley, D., Pruss, C.M., Nguyen, T.T., Silverman, C.L., Lin-Goerke, J., Khandekar, S., Liu, C., Baker, A.E., Casper, D.J., and R.T. Sarisky.  Mapping cooperative activity of the hepatitis C virus RNA-dependent RNA polymerase using genotype 1a-1b chimeras. B BRC, 313:343-50, 2004.

18. Mehta, A.S., Gu, B., Conyers, B., Ouzounov, S., Wang, L., Romano, R.,  Moriarty, RM., Dwek, R.A., and T.M. Block.  Alpha galactosyl ceramide and novel synthetic glycolipids induce the innate host defense pathway and have direct anti-viral activity against hepatitis B and C viruses. Antimicrob Agents Chemother., 48: 2085-90, 2004.

19. Gu, B., C. Pruss, A. Gates and S. Khandekar.  The RNA-unwinding activity of Hepatitis C virus non-structural protein 3 (NS3) is modulated by its proteinase domain.  Curr. Prot. and Peptide Ltrs., (accepted).

20. Chapman, T.M., Davies, I.G., Gu, B., Block, T.M., Scopes, I.C., Hay, P.A., Courtney, S.M., McNeill, L.A., Schofield, C.J., and B.G. Davis.   Glyco- and peptido-mimetic inhibitors using a three-component joullié-ugi reaction.  J. Amer. Chem. Soc., (accepted).