Peng Laboratory --The Relationship of Host Lipid Metabolism to Hepatitis C Infection

We have discovered that the cholesterol biosynthetic pathway is critically important to the hepatitis C viral lifecycle and are examining this relationship further.

Hepatitis C virus (HCV) infects over 170 million people worldwide and can lead to cirrhosis, liver failure, and liver cancer. The current medications that we have for the treatment of hepatitis are imperfect.

Finding better drugs for the treatment of HCV is therefore a priority. The study of factors that regulate the viral lifecycle, of which host lipid biosynthesis is one, can help us better understand the virus to combat infection.

The identification of biomarkers prognositic of outcome in chronic HCV infection can help guide therapeutic decision making. The examination of the mechanism of action of our anti-viral compounds can not only be used as a method to characterize key interactions and pathways critical to viral replication, but can be a productive means to the discovery of potential antiviral agents for the treatment of chronic HCV infection.

 

  1. Define the role through which miR-122, apoB100, and host lipid metabolism interact to promote HCV infection.
  2. Assess alteration of infectivity of HCV virions by statins and HMG-CoA synthase inhibitors.
  3. Identify biomarkers for prognostication of outcome in chronic HCV infection using lipidomic assessment of HCV-infected cell lines, serum, and liver tissue.

  1. Shi, Y., Peng, L. F., Kishi, Y. Enantioselective Total Synthesis of Fumonisin B2. J. Org. Chem., 1997, 62, 5666.
  2. Kim, Sun Suk; * Peng, Lee F.; * Lin, Wenyu; Choe, Won-Hyeok;  Sakamoto, Naoya; Schreiber, Stuart L.; Chung, Raymond T.  A Cell-Based, High-Throughput Screen for Small Molecule Regulators of HCV Replication.  Gastroenterology, 2007, 132(1), 311-320. * S.S.K. and L.F.P. contributed equally to this project.
  3. Peng, Lee F.; * Kim, Sun Suk;* Matchacheep, Sirinya; Lin, Wenyu; Choe, Won-Hyeok;  Sakamoto, Naoya; Schreiber, Stuart L.; Chung, Raymond T.  Identification of Novel Epoxide Inhibitors of HCV Replication Via High-Throughput Screening. Antimicrobial Agents and Chemotherapy 2007, 51: 3756-3759. * L.F.P. and S.S.K. contributed equally to this project.
  4. Lin, W.;  Weinberg, E. M.; Tai, A. W.;  Peng, L. F.; Brockman, M. A.; Kim, K. A.; Kim,  S.S.; Borges, C. B.; Shao,  R. X.; Chung, R. T. HIV increases HCV replication in a TGF-beta1-dependent manner. Gastroenterology, 2008, 134(3), 803-811.
  5. Tai, Andrew W.; Benita, Yair; Peng, Lee F.; Kim, Sun-Suk; Sakamoto, Naoya; Xavier, Ramnik J.; Chung, Raymond T. A functional genomic screen identifies cellular cofactors of hepatitis C virus replication. Cell Host and Microbe, 2009, 5: 298-307.
  6. Stanton, Benjamin Z.;* Peng, Lee F.;*  Maloof, Nicole; Nakai, Kazuo; Wang, Xiang; Duffner, Jay L.; Taveras, Kennedy; Hyman, Joel M.; Lee, Sam W.; Koehler, Angela N.; Chen, James K.; Fox, Julia L.; Mandinova, Anna; Schreiber, Stuart L.  Discovery and characterization of a small molecule that inhibits Sonic Hedgehog (Shh) activity. Nature Chemical Biology, 2009, 5: 154-156.* B.Z.S. and L.F.P. contributed equally to this project. L.F.P. was corresponding author on this publication.
  7. Chen, Shuibing; Borowiak, Malgorzata; Fox, Julia L.; Maehr, Rene; Osafune, Kenji; Davidow, Lance; Lam, Kelvin; Peng, Lee F.; Schreiber, Stuart L.; Rubin, Lee L.; Melton, Douglas. A small molecule that directs differentiation of human embryonic stem cells into the pancreatic lineage.  2009. Nature Chemical Biology, 5: 258-265.
  8. Peng, Lee F.;*  Stanton, Benjamin Z.;* Maloof, Nicole; Nakai, Kazuo; Wang, Xiang; Chen, James K.; Schreiber, Stuart L.  Syntheses of aminoalcohol-derived macrocycles leading to a small-molecule binder to and inhibitor of Sonic Hedgehog. Bio-organic and Medicinal Chemistry Letters, 2009, 19:6319-25. * L.F.P. and B.Z.S. contributed equally to this project. L.F.P. was corresponding author on this publication.
  9. Lin, Wenyu; Tsai, W. L.; Shao, R. X.; Wu, G.; Peng, Lee F.; Barlow, L. L.; Chung, W. J.; Zhang, L.; Zhao, H.; Jang, J. Y.; Chung,  R.T. Hepatitis C virus regulates transforming growth factor beta1 production through the generation of reactive oxygen species in a nuclear factor kappaB-dependent manner. Gastroenterology, 2010, 138(7):2059-2518.
  10. Shao, R. X.; Zhang, L.; Peng, L. F.; Sun, E.; Chung, W. J.; Jang, J. Y.; Tsai, W.L.; Hyppolite, G.; Chung, R .T. Suppressor of cytokine signaling 3 suppresses hepatitis C virus replication in an mTOR-dependent manner. J. Virology, 2010, 84(12): 6060-6069.
  11. Zhang, L.; Jilg, N.; Shao, R.X.; Lin, W.; Fusco, D. N.; Zhao, H.; Goto, K.; Peng, Lee F.; Chen, W.-C.; Chung, R. T. IL28B inhibits Hepatitis C virus replication through the JAK-STAT pathway. J. Hepatology, 2011, 55(2): 289-298.
  12. Jang J.Y.; Shao, R.X.; Lin, W.; Weinberg, E.; Chung, W.J.; Tsai, W.L.; Zhao, H.; Goto, K.; Zhang, L.; Mendez-Navarro, J.; Jilg, N.; Peng, Lee F., Brockman, M.A.; Chung, R.T. HIV infection increases HCV-induced hepatocyte apoptosis. J. Hepatology, 2011, 54(4): 612-620.
  13. Lin, W.; Wu, G.; Li, S.; Weinberg, E.M.; Kumthip, K.; Peng, Lee F.; Méndez-Navarro, J.; Chen, W.C.; Jilg, N.; Zhao, H.; Goto, K.; Zhang, L.; Brockman, M.A.; Schuppan, D.; Chung, R.T. HIV and HCV cooperatively promote hepatic fibrogenesis via induction of reactive oxygen species and NFkappaB. J. Biol. Chem., 2011, 286(4):2665-74.
  14. Peng, Lee F.; Schaefer, Esperance; Maloof, Nicole; Skaff, Andrew; Berical, Andrew; Belon, Craig A.; Heck, Julie A.; Lin, Wenyu; Frick, David N.; Allen, Todd M.; Miziorko, Henry; Schreiber, Stuart L.; Chung, Raymond T.  Ceestatin, a novel small molecule inhibitor of hepatitis C virus replication, inhibits HMG-CoA synthase. Journal of Infectious Disease, 2011, 204: 609-616.
  15. Zhao, H.; Lin, W.; K. Kumthip, K; Cheng, D.; Fusco, D.N.; Hofmann, O.; Jilg, N.; Tai, A.W.; Goto, K. Zhang, L.; Hide, W.; Jang, J.Y.; Peng, L.F.; Chung, R.T. A functional genomic screen reveals novel host genes that mediate interferon-alpha’s effects against hepatitis C virus. J Hepatol., 2012, 56 (2): 326-333.
  16. Rodgers M.A.; Villareal, V.A.; Schaefer, E.A.; Peng, L.F.; Corey, K.E.; Chung, R.T.; Yang, P.L. Lipid Metabolite Profiling Identifies Desmosterol Metabolism as a New Antiviral Target for Hepatitis C Virus. J Am Chem Soc., 2012, 134(16): 6896-9.
  17. Kumthip K, Chusri P, Jilg N, Zhao L, Fusco DN, Zhao H, Goto K, Cheng D, Schaefer EA, Zhang L, Pantip C, Thongsawat S, O'Brien A, Peng LF, Maneekarn N, Chung RT, Lin W. Hepatitis C virus NS5A disrupts STAT1 phosphorylation and suppresses type I interferon signaling. J. Virol., 2012, 86(16):8581-91.
  18. Shao RX, Zhang L, Hong Z, Goto K, Cheng D, Chen WC, Jilg N, Kumthip K, Fusco DN, Peng LF, Chung RT. SOCS1 abrogates IFN's antiviral effect on hepatitis C virus replication. Antiviral Res., 2013, 97(2):101-7.
  19. Ding Q, Lee YK, Schaefer EA, Peters DT, Veres A, Kim K, Kuperwasser N, Motola DL, Meissner TB, Hendriks WT, Trevisan M, Gupta RM, Moisan A, Banks E, Friesen M, Schinzel RT, Xia F, Tang A, Xia Y, Figueroa E, Wann A, Ahfeldt T, Daheron L, Zhang F, Rubin LL, Peng LF, Chung RT, Musunuru K, Cowan CA. A TALEN Genome-Editing System for Generating Human Stem Cell-Based Disease Models. Cell Stem Cell, 2013, 12(2):238-51.
  20. Fusco DN, Brisac C, John SP, Huang YW, Chin CR, Xie T, Zhao H, Zhang L, Chevalier S, Wambua D, Lin W, Peng L, Chung RT, Brass AL. A Genetic Screen Identifies Interferon-α Effector Genes Required to Suppress Hepatitis C Virus Replication. Gastroenterology, 2013, 144(7): 1438-49.
  21. Goto K, Lin W, Zhang L, Jilg N, Shao RX, Schaefer EA, Zhao H, Fusco DN, Peng LF, Kato N, Chung RT. The AMPK-related kinase SNARK regulates hepatitis C virus replication and pathogenesis through enhancement of TGF-β signaling. J. Hepatol, 2013, 59(5):942-8.
  22. Jilg N, Lin W, Hong J, Schaefer EA, Wolski D, Meixong J, Goto K, Brisac C, Chusri P, Fusco DN, Chevaliez S, Luther J, Kumthip K, Urban TJ, Peng LF, Lauer GM, Chung RT. Kinetic differences in the induction of interferon stimulated genes by interferon-α and interleukin 28B are altered by infection with hepatitis C virus. Hepatology, 2014, 59(4): 1250-1261.