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National Yang-Ming University

Szu-Hao Kung

Associate Professor

 

龔思豪     

Szu-Hao Kung

 

 

 
 
 
Contact   Education

Office: Research Building Room 316

Phone(02)2826-7034 (office) (02)2826-7000 #5829 (lab)

E-mail: szkung@ym.edu.tw

 

 

Ph.D., University of South Florida

B.S., National Yang-Ming University

 
 
Research Interest
  1. Discovery of drugs for enterovirus infections and identification of the action mechanisms –A real-time screening platform for anti-enterovirus drugs has been developed by us. This is based on the conversion of fluorescence resonance energy transfer (FRET) upon enteroviral infections. By this system, we have uncovered several compounds with strong antiviral activities. For example, idarubicin, a clinically used anti-cancer drug, was identified as a specific viral translation blocker. We are in the process of identifying the action modes of several other compounds. Because many of them are FDA-approved drugs, a drug repurposing approach is implemented to identify new indications of them. This would shorten the development timeframe for the enterovirus therapeutics. The collection of these novel antivirals have been submitted for patent application.

         

Fig. 1.Principle of the FRET-based screen. FRET occurs when the FRET pair is in close proximity until the action of the viral protease in the context of EV71 replication that leads to cleavage, separation of the FRET pair and the consequent FRET disruption. On the other hand, FRET remains intact when EV71 replication is blocked by a test compound. GFP2=green fluorescence protein; DsRed2= red fluorescence protein; CM=cleavage motif. 

  1. Molecular basis for enterovirus replication and pathogenesis –Host cell calcium (Ca2+) signals are increasingly recognized to play important roles in steps of viral entry, replication, and transmission for a range of viruses. Indeed, studies from some enterovirus species showed that enterovirus infections resulted in decreased endothelium reticulum Ca2+ stores and activation of extracellular Ca2+ influx, ultimately causing an elevation in intracellular Ca2+. Elevated intracellular Ca2+ is absolutely required for virus replication, but the underlying molecular mechanisms responsible for Ca2+ flux remain poorly understood. We are in the process of unfolding the virus-induced Ca2+ channels and Ca2+ signals implicated in enterovirus replication and cytopathology (caused by the viral spread). Host Ca2+ channels and Ca2+ signaling pathways may serve as potential therapeutic targets, and we have identified some Ca2+ channel blockers that display anti-enterovirus activities.

  

Fig. 2. Schematic representation of enterovirus-induced Ca2+ signals that could be implicated in viral replication and viral spread through alterations in cell proliferation, cytoskeleton, autophagy, apoptosis and necrosis. [Ca2+ ]C= cytosolic Ca2+ concentration; [Ca2+ ]ER= endothelium reticulum Ca2+ concentration.

 
Representative Publications

  1. Chen KR, Yu CK, Kung SH, Chen SH, Chang CF, Ho TC, Lee YP, Chang HC, Huang LY, Lo SY, Chang JC, Ling P. (2018). Toll-like receptor 3 is involved in detection of enterovirus A71 infection and targeted by viral 2A protease. Viruses. 2018.10(12). E689.
  2. Lu WW, Kung FY, Deng PA, Lin YC, Lin CW, Szu-Hao Kung (2017). Development of a fluorescence resonance energy transfer–based intracellular assay to identify novel enterovirus 71 antivirals. Archives of Virology. 162(3):713-720.
  3. Hou HY, Lu WW, Wu KY, Lin CW, Kung SH (2016). Idarubicin is a broad-spectrum enterovirus replication inhibitor that selectively targets the virus internal ribosomal entry site. J Gen Virol. 97(5): 1122-33.
  4. Lu WW, Kung FY, Deng PA, Lin YC, Lin CW, Kung SH. (2017). Development of a fluorescence resonance energy transfer–based intracellular assay to identify novel enterovirus 71 antivirals. Arch. Virol. 162 (3): 713-720.
  5. Wang CY, Huang AC, Hour MJ, Huang SH, Kung SH, C Chen CH, Chen IC, Chang YS, CW Lin (2015). Antiviral Potential of a Novel Compound CW-33 against Enterovirus A71 via Inhibition of Viral 2A Protease. Viruses. 7, 3155-3171.
  6. Lu JR, Lu WW, Lai JZ, Tsai FL, Wu SH, Lin CW, Kung SH. (2013) Calcium flux and calpain-mediated activation of the apoptosis-inducing factor contribute to enterovirus 71-induced apoptosis. J Gen Virol. 94(7):1477-85.
  7. Lu WW, Sun JR, SS Wu, Lin WH, Kung SH (2011). A dual reporter cell assay for identifying serotype and drug susceptibility of herpes simplex virus. Analytical Biochemistry. Aug 15;415(2):97-104.
  8. Li SW, Lai CC, Ping JF, Tsai FJ, Wan L, Lin YJ, Kung SH, Lin CW. (2011). Severe acute respiratory syndrome coronavirus papain-like protease suppressed alpha interferon-induced responses through downregulation of extracellular signal-regulated kinase 1-mediated signalling pathways. Journal of General Virology. 92:1127-40.
  9. Hsu YY, Liu YN, Lu WW, Kung SH. (2009). Visualizing and quantifying the differential cleavages of the eukaryotic translation initiation factors eIF4GI and eIF4GII in the enterovirus-infected cell. Biotechnol Bioeng. 104(6):1142-52. 
  10. Tsai MT, Cheng YH, Liu YN, Liao NC, Lu WW, Kung SH. (2009). Real-time monitoring of human enterovirus (HEV)-infected cells and anti-HEV 3C protease potency by fluorescence resonance energy transfer. Antimicrob Agents Chemother. 53(2):748-755. 
  11. Hsu YY, Liu YN, Wang W, Kao FJ, and Kung SH. (2007). In Vivo Dynamics of Enterovirus Protease Revealed by Fluorescence Resonance Emission Transfer (FRET) based on a novel FRET pair. Biochem Biophys Res Commun. 353, 939–945. 
  12. Kung SH, Wang SF, Huang CW, Hsu CC, Liu HF, Yang JY. (2007). Genetic and antigenic analyses of enterovirus 71 isolates in Taiwan during 1998-2005. Clin Microbiol Infect. 13(8):782-7. 
  13. Ghukasyan V, Hsu YY, Kung SH, Kao FJ. (2007). Application of fluorescence resonance energy transfer resolved by fluorescence lifetime imaging microscopy for the detection of enterovirus 71 infection in cells. J Biomed Opt. 12(2):024016.
  14. Lu WW, Hsu YY, Yang JY, Kung SH. (2004). Selective inhibition of enterovirus 71 replication by short hairpin RNAs. Biochem Biophys Res Commun. 325(2):494-9.1998-2002
  15. Kuo YC, Lin LC, Tsai WJ, Chou CJ, Kung SH, Ho, YH.. Samarangenin B from Limonium sinense suppresses herpes simplex virus type 1 replication in Vero cells by regulation of viral macromolecular synthesis. Antimicrobial Agents and Chemotherapy 2002;46(9):2854-2864
  16. Y-C Wang, C-L Kao, W-T Liu, J-R Sun, Y-E Tai, and Kung SH. A Cell Line That Secretes Inducibly a Reporter Protein for Monitoring Herpes Simplex Virus Infection and Drug Susceptibility. Journal of Medical Virology 2002;68(4):599-605.
  17. Kuo, RL, Kung, S.H., Hsu, YY, and Liu, WT. Infection with Enterovirus 71 or expression of its 2A protease induces apoptotic cell death. Journal of General Virology 2002;83:1367-1376.
  18. Tai, H.Y., Sun, K.H., Kung, S.H., Liu, W.T. A quantitative assay for measuring human foamy virus using an established indicator cell line. Journal of Virological Methods 2001;94:155-162.
  19. Liu, W.T., Sun, JR, Lin, CH, Kuo RL, and Kung SH.. An indicator cell assay for detection of human cytomegalovirus based on enhanced green fluorescent protein. Journal of Virological Methods 2001;96:85-92.
  20. Kung, S.H., Wang, Y.C., Lin, C.H., Kuo, R.L., and Liu, W.T. Rapid diagnosis and quantification of herpes simplex virus with a green fluorescent protein reporter system. Journal of Virological Methods 2000;90:205-212.
  21. Kung, S.H., Hagstrome, J.N., Cass, D., Tai, S.J., Lin, H.F., Stafford, D. and High K.A.. Human coagulation factor IX corrects the bleeding diathesis of mice with hemophilia B. Blood 1998;91:784-790.
  22. Nakai, H., Herzog, R.H., Hagstrome, J.H., Walter, J.H., Kung, S.H., Yang, E.Y., Tai, S.H., Iwaki, Y., Kurtzman, G.J., Fisher,K.J., Colosi,P., Couto, L.B., and High, K.A.. Adeno-associated viral vector-mediated gene transfer of human blood coagulation factor IX into mouse liver. Blood 1998;91:4600-4607.
  23. Herzog, R.W., Hagstrome, J.N., Kung, S.H., Tai, S.J., Wilson, J.M., Fisher, K. J., and High, K.A. Stable gene transfer and expression of human blood coagulation factor IX after intramuscular injection of recombinant adeno-associated virus. Proceedings of the national academy of sciences of the United States of America 1997;94:5804-5809.
  24. Kung, S.H. and Medveczky, P. Identification of a Herpesvirus saimiri cis-acting DNA fragment that permits stable replication of episomes in transformed T cells. Journal of Virology 1996;70:1738-1744.