Sigma-Aldrich Lecture: Dr. Martin Burke - Making Molecular Prosthetics with a Small Molecule Synthesizer

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.

References
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Antimicrobials that Evade Drug Resistance" Nat. Chem. Bio. 2015, 11, 481.
(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.
(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.
(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,
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(8) J. Li, M.D. Burke. J. Am. Chem. Soc. 2011, 133, 13774.
(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.
(10) E.M. Woerly, A.H. Cherney, E.K. Davis, M.D. Burke. J. Am. Chem. Soc. 2010, 132, 6941-6943.