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Developing Synthetic Molecules to Defeat Bioterrorism

Developing Synthetic Molecules to Defeat Bioterrorism. Bioterrorism. “Greatest threat to life on Earth” Doomsday Scenario: biological agents released from plane Biologists: “main difficulty” of terrorists not acquiring agent FAS: available on eBay.

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Developing Synthetic Molecules to Defeat Bioterrorism

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  1. Developing Synthetic Molecules to Defeat Bioterrorism

  2. Bioterrorism • “Greatest threat to life on Earth” • Doomsday Scenario: biological agents released from plane • Biologists: “main difficulty” of terrorists not acquiring agent • FAS: available on eBay Butler, Richard. The Greatest Threat. New York: Public Affairs, 2000 Yetiv, Steve A. The Persian Gulf Crisis. London: Greenwood Press, 1997. Snell, Noel. 2002. Bioterrorism Today. Biologists 140. http://www.usatoday.com/news/opinion/editorials/2004-11-21-bioterrorism_x.htm

  3. http://oregonconservative.blogspot.com/2004/11/marlboro-man-kicks-butt-or-smokin.htmlhttp://oregonconservative.blogspot.com/2004/11/marlboro-man-kicks-butt-or-smokin.html

  4. http://www.llnl.gov/cbbb/balhorn.html

  5. Current Detection Methods • Immunoassays used to detect pathogens • Small amount of DNA • Rapid variation • Small amount acutely toxic

  6. Review • The Problem: Bioterrorism is a threat to humanity, but current detection techniques are insufficient.

  7. Synthetic Molecules? • Seek-and-destroy : Antibodies in body zero in on specific proteins • Target unique site • Active site not a target

  8. High Affinity Ligands (HALs) • Ligand used instead of antibody • Bidentate Ligand

  9. Advantages of HALs • Potential to be completely inorganic • Large quantities maintain functional and structural identities • Enduring stability

  10. Can it work? • Clostridium Neurotoxins studied • Structure has three parts

  11. Finding a Bonding Site

  12. Computer Modeling to Determine HALs • Computationally tested compounds from the Available Chemicals Database • Top 1000 were selected for more vigorous testing • Narrowed to 100

  13. Review • Two bonding sites were found on the tetanus toxin and after computer modeling 100 possible ligands showed potential to bind to the sites.

  14. Picking the HAL • Used mass spectrometry to find the best 34 of the 100 • Anti-tumor drug doxorubicin found to be best fit at site one • 11 selected for additional testing

  15. Testing the Site 2 Ligands • NMR was used • 4 Ligands determined to bind to toxin, 3 at site two • Site 1 binder, doxorubicin, remained bonded while other ligands bonded • Found strongest interaction was doxorubicin-lavendustin A (MP-biocytin second)

  16. Site 1 Site 2

  17. Linking the Ligands • Individual ligands bond fairly weakly to toxin • Linking the two molecules would increase likelihood they remain bound

  18. Linking the Ligands • Starting with Lysine • Glycol chain to increase distance

  19. Cancer • Must bind to tumor cells without generating immune reaction http://www.llnl.gov/cbbb/research-3.html

  20. Future Directions and Conclusions • Successfully bonded two novel small molecules to two different sites on the surface of tetanus toxin • Other biological weapons

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