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Unformatted text preview: Antiviral Treatment Through Chemotherapeutic Kinase Inhibitors
Anish Gupta & Jason Rose BME 321: Bioreaction Engineering University of Michigan Smallpox
Very Lethal (1/3*) Highly Contagious Susceptibility BIOTERRORIS M Current Smallpox Treatment & Prevention
Safety Issues Expensive Short Immunity NO TREATMENT NEED BETTER METHOD The Viral “Attack” Cannot Reproduce by Themselves “Hijack” a cell’s own machinery Lytic Cycle Infection Mechanism EGF binds RTK (normal) Signal Cascade Induces Proliferation Virus encodes EGFlike factor (SPGF) Increases Viral Transcription
– – Binds ErbB RTK Autocrine Loop – Transcription factors Increased Activity Receptor Mediated Endocytosis ~ “OFF” SPGF does NOT induce Receptor ~ stays “ON” Overexpressed Viral Products/Proliferation
– Ubiquitylation Similar to Cancer Mechanisms Antiviral Chemotherapy Cancer same problem – Protooncogenes (RTKs) overexpressed
Cannot turn “OFF” Chemotherapy targets these proteins Can CHEMOTHERAPY be used to target viral infections? Chemotherapeutic Agents Tyrosine Kinase Inhibitors – Block nucleotide binding site of Kinase – Enhance ubiquitylation Candidate: CI1033 – Irreversible Inhibitor – Alkylates a Cys specific to ErbB receptors Experiment 1 GOAL: Identify the inhibitors of SPGF – Pretreat cells with inhibitors – Stimulate cells with SPGF – Test for inhibition Exp 1: Results CI1033 and PD168393 both inhibit SPGF Experiment 2 GOAL: Find effect of CI1033 on Orthopox Virus – Variola Virus Monkey kidney cells – Vary concentrations of CI1033 – Measure growth of virus Exp 2: Results
•Significant decrease in number of comets but not plaques •Shows virus does not spread Experiment 3 GOAL: Prove inhibitor rescues mice with pneumonia – Virulence control – Administer CI1033 at varying times and durations – Chart both survival rate and lung weight Exp 3: Results Treatment with drug alone consistently inhibits death Treatment in combination with Anti L1R also clears mucus filled lungs Why Three Experiments? Exp1: CI1033 effectively inhibits SPGF binding to ErbB1 MOLECULAR Exp2: CI1033 stops the spread of virus to other cells in vitro VIRAL Exp3: CI1033 prevents disease development, clears pneumonia from lungs LIVING ORGANISM Take Home Messages: Cell Signal Inhibitor STOP Viral Infection Current cancer drugs work – Treatment NOT prevention – Virus cannot develop Immunity – No Development Cost/Time Reference Articles
Yang, H., et al. Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction. J Clin Invest. 2005 Feb; 115(2):37987. Kim, M., et al. Biochemical and Functional Analysis of Smallpox Growth Factor (SPGF) and AntiSPGF Monoclonal Antibodies. J. Biol. Chem. 2004; 279:2583825848. Citri, A., et al. Druginduced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy. EMBO. 2002; 21:24072417. Tzahar, E., et al. Pathogenic poxviruses reveal viral strategies to exploit the ErbB signaling network. EMBO. 1998; 17:59485963. Seger, R. and Krebs, E. The MAPK signaling cascade. FASEB J. 1995; 9:726 735. Thanks for your attention Any Questions? Discussion CI1033 does not destroy virus Not useful for chronic viral diseases (deters proliferation, does not cure) Orthopox family and erbB receptor viruses all could be stopped via the signalblocking technique Significance Bioterrorism Roundabout approach – shortcircuits signaling pathways rather than attack the virus itself Opens the door for developing other signal inhibiting pathways for viral treatment Relevance Cell signaling pathways involve multi enzyme systems Drug synthesis Won’t blocking a cell pathway be harmful to the host? For short time intervals, blockade of selective cell function is feasible. Our Critique Interesting article A lot of research left to do…a lot of the results are not significant. FDA Approval for Marketable Drug
– Further Smallpox Research – Human Trials Treating other viruses? Very possible Testing did show affects pneumonia Other viruses use simliar mechanisms
– Shope fibroma virus (SFGF) – Myxoma virus (MGF) – Vaccinia virus (VGF) Additional References
http://www.med.umich.edu/opm/newspage/2002/smallpoxvac.htm http://www.vechirka.com.ua/events/world/bioweapon.jpg http://www.afscme.org/health/faqspx2.htm http://www.bt.cdc.gov/agent/smallpox/overview/diseasefacts.asp http://www.emedicine.com/emerg/topic885.htm http://webs.wichita.edu/mschneegurt/biol103/lecture12/smpox.jpg http://www.cwru.edu/artsci/dittrick/smallpox/diseasedescrption.htm http://www.people.virginia.edu/~rjh9u/rtksignal.html http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CellSignaling.html http://cbw.sipri.se/images/intro/smallpoxc.jpg http://www.uic.edu/classes/bios/bios100/mike/spring2003/tk02.jpg http://wps.prenhall.com/wps/media/objects/488/499792/images/AABXJOV0a.jpg http://skincare.healthcares.net/smallpoxspread.php http://www.chemsoc.org/exemplarchem/entries/2003/imperial_Burgoine/cancer_cell_division.jpg ...
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- Winter '08