05-0324PRESENTJClinInvestViralInhibitEGFSPathway-AnishJasonAntiVirus+(2)

05-0324PRESENTJClinInvestViralInhibitEGFSPathway-AnishJasonAntiVirus+(2)

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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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