Prof. Martin Burke


Prof. Martin Burke
Tuesday May 23rd




Making Molecular Prosthetics 

Abstract

Small molecules that bind to proteins can serve as powerful medicines. However, diseases caused by deficiencies of protein function are generally refractory to this classic approach. Fortunately, nature has provided inspiration for an alternative strategy in the form of small molecules that can autonomously perform higher-order, protein-like functions in the context of living systems. The existence of these natural prototypes suggests that small molecules may possess untapped potential to replace deficient proteins that underlie human diseases, thereby operating as prostheses on the molecular scale. This lecture will describe how recent advances in synthetic organic chemistry have played a major role in understanding and utilizing these molecules. Specifically, analogous to peptide synthesis, iterative cross-coupling with MIDA boronates has emerged as an increasingly general and now fully automated way to prepare complex small molecules with maximized efficiency and flexibility, thereby enabling systematic studies of their functions. Collectively, these advances are transforming molecular prosthetics into a powerful and general strategy for promoting the understanding and betterment of human health.





Biography

Marty completed his undergraduate degree in chemistry at Johns Hopkins University in 1998, a Ph.D. in organic synthesis at Harvard University in 2003, and an M.D. at Harvard Medical School in 2005. He is now a Professor in the Department of Chemistry at the University of Illinois at Urbana-Champaign. Marty’s research focuses on small molecules that replicate the functions of missing proteins, thereby operating as prostheses on the molecular scale. To enable such studies, Marty's group created a machine that builds molecules from pre-fabricated building blocks. This advance helps make the process of complex small molecule synthesis as simple, efficient, and flexible as possible. Utilizing this building block chemistry, his group illuminated the mechanism by which the ion channel forming natural product amphotericin exerts its cytocidal activities. This mechanistic understanding enabled his group to discover the first derivatives of amphotericin that are toxic to yeast but not human cells and test the capacity of this small molecule to replicate the function of missing protein ion channels. Many MIDA boronate building blocks are now commercially available, and Marty recently co-founded a new biotech company, called REVOLUTION Medicines, which is industrializing the MIDA boronate synthesis platform to re-engineer evolution’s products into new medicines for serious human diseases, including developing optimal drug candidates from amphotericin B. Marty is the recipient of a number of honors and awards, including the 2014 Thieme-IUPAC Prize in Synthetic Organic Chemistry, The 2014 Hirata Gold Medal from Japan, the 2013 American Chemical Society Elias J. Corey Award for Outstanding Original Contribution in Organic Synthesis by a Young Investigator, a Howard Hughes Medical Institutes Early Career Scientist Award, the 2013 Kavli Foundation Emerging Leader in Chemistry Award, the American Chemical Society Arthur C. Cope Scholar Award, the Arnold and Mabel Beckman Foundation Young Investigator Award, a Sloan Foundation Research Fellowship, an NSF CAREER award, the Dreyfus Foundation New Faculty Award, the Bristol-Myers Squibb Unrestricted Research Grant in Synthetic Organic Chemistry, the Novartis Chemistry Lectureship, the Eli Lilly Grantee Award, the Amgen Young Investigator Award, the AstraZeneca Excellence in Chemistry Award, and he has been named one of the world's 35 top innovators under age 35 by Technology Review. He has also been recognized many times by the University of Illinois Center for Teaching Excellence.







References

(1)  Davis, S. A.; Vincent, B. M.; Endo, M. M.; Whitesell, L.; Marchillo, K.; Andes, D. R.; Lindquist, S.; Burke, M. D. "Nontoxic Antimicrobials that Evade Drug Resistance" Nat. Chem. Bio. 2015, 11, 481-487.

(2)  Li, J.; Ballmer, S. G.; Gillis, E. P.; Fujii, S.; Schmidt, M. J.; Palazzolo, A. M. E.; Lehmann, J. W.; Morehouse, G. F.; Burke, M. D. "Synthesis of Many Different Types of Organic Small Molecules Using One Automated Process" Science 2015, 347, 1221-1226.

(3)  E.M. Woerly, J. Roy, M.D. Burke, Nature Chemistry 2014, 6, 484-491.

(4)  T.M. Anderson, M.C. Clay, A.G. Cioffi, K.A. Diaz, G.S. Hisao, M.D. Tuttle, A.J. Nieuwkoop, G. Comellas, S. Wang, B.E. Uno, E.L. Wildeman, N. Maryum, T. Gonen, C.M. Rienstra, M.D. Burke. Nature Chemical Biology, 2014, 10, 400-406.

(5)  Wilcock, B. C.; Endo, M. M.; Uno, B. E.; Burke, M. D. J. Am. Chem. Soc. 2013, 135, 8488-849.

(6)  Wilcock, B. C.; Uno, B. E.; Bromann, G. L.; Clark, M. J.; Anderson, T. M.; Burke, M. D. Nature Chemistry 2012, 4, 996-1003.

(7)  K.C. Gray, D.S. Palacios, I. Dailey, M.M. Endo, B.E. Uno, B.C. Wilcock, M.D. Burke. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 2234-2239.

(8)  J. Li, M.D. Burke. J. Am. Chem. Soc. 2011, 133, 13774-13777.

(9)  D.S. Palacios, I. Dailey, D.M. Siebert, B.C. Wilcock, M.D. Burke. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6733-6738.

(10)        E.M. Woerly, A.H. Cherney, E.K. Davis, M.D. Burke. J. Am. Chem. Soc. 2010, 132, 6941-6943.