Expanding the Range of Native Chemical Ligations

1. Expanding the Range of Native Chemical Ligations Aaron Crapster Under the Supervision of Helen Blackwell March 5, 2009

2. Need for Chemical Synthesis of Proteins Kent, S. B. H. Chem. Soc. Rev.2009, 38, 338.

3. Chemical Synthesis of Proteins Kent, S. B. Chem. Soc. Rev.2009, 38, 338.

4. Significance to Pharmaceutical Industry Bray, B. Nature Rev. Drug Discovery2003, 2, 587.

5. Classical Amide-Bond Formation Marder, O.; Albericio, F. ChemiciaOggi2003, 35-40.

6. Limitations of Classical Approach Bode, J. Curr. Opin. Drug Discovery Dev.2006, 9, 765.; Benoiton, N.L. Chemistry of Peptide Synthesis. Taylor & Fracis Group; Boca Raton, FL, 2006.

7. Ideal Fragment Coupling Hackenberger, C. P. R.; Schwarzer, D. Angew. Chem. Int. Ed. 2008, 47, 10030.

8. The Basis of Native Chemical Ligation Wieland, T. et al. Justus Liebigs Ann. Chem.1953, 583, 129.

9. The Potential of NCL is Realized Dawson, P.E. et al. Science1994, 266, 776.

10. Requirements for NCL Camarero, J.A.; Mitchell, A.R. Protein & Peptide Lett.2005, 12, 723.;

11. Aryl Thiols Added as Catalysts Johnson, E. C. B.; Kent, S. B. H. JACS2005, 128, 6640.

12. Influence of C-Terminal Residue Hackeng, T. M.; Griffin, J. H.; Dawson, P.E. Proc. Natl. Aced. Sci. 1999, 96, 10068.

13. Native Chemical Ligation

14. Post-Ligation Modifications to Cysteine Hackenberger, C. P. R.; Schwarzer, D. Angew. Chem. Int. Ed.2008, 47, 10030.; Yan, L. Z.; Dawson, P. E. JACS2001, 123, 526.

15. Uncovering a Serine Ligation Site Okamoto, R.; Kajihara, Y. Angew. Chem. Int. Ed. 2008, 47, 5402.

16. Metal-Free Desulfurization Wan, Q.; Danishefsky, S. J. Angew. Chem. Int. Ed.2007, 46, 9248.

17. Wan, Q.; Danishefsky, S. J. Angew. Chem. Int. Ed.2007, 46, 9248.

18. Utility of Free-Radical Desulfurization Haase, C.; Rohde, H.; Seitz, O. Angew. Chem. Int. Ed.2008, 47, 6807.

19. Other Alternatives to Cysteine

20. Side-Chain Auxiliary Brik, A. et al. JACS2006, 128, 5626.

21. Scope of Sugar-Assisted Ligation Brik, A. et al. JACS2006, 128, 5626.; Brik, A. et al. JACS2006, 128, 15026.

22. Acid Labile N-linked Auxiliary MacMillan, D.; Anderson, D.W.; Org. Lett.2004, 6, 4659.

23. The Scope of This Auxiliary Botti, P. Tetrahedron Lett.2001, 42, 1831; Low, D.W. PNAS2001, 6554.

24. o-Nitrobenzyl (Veratryl) Auxiliary Marinizi, C. et al. Bioorg. Med. Chem. 2004, 12, 2749.

25. Limited Scope of Veratryl Auxiliary Marinizi, C. et al. Bioorg. Med. Chem. 2004, 12, 2749.

26. Site-Specific Peptide Ubiquitylation Chatterjee, C. et al. Angew. Chem. Int. Ed. 2007, 46, 2814.

27. Pushing Back the Limits

28. Expanding Chemoselective Ligations Bode, J. W.; Fox, R. M.; Baucom, K. D. Angew. Chem. Int. Ed. 2006, 45, 1248.

29. Acknowledgements Helen E. Blackwell Special Thanks To: Kat Myhre Practice Talk Attendees: Aaron Almeida Jay Steinkruger Shane Mangold Chris Brown Brian Esselman Ben Case Daria Fedyukina The Blackwell Lab Joey Stringer Knick Praneenararat Christie McInnis Teresa Beary Tony Breitbach Margie Mattmann J.P. Gerdt Drew Palmer Danielle Stacey