Research on molecular prosthetics—the use of small molecules that carry out proteinlike functions to cure human diseases—and groundbreaking advances in the field of organic synthesis have earned assistant professor Martin D. Burke of the University of Illinois, Urbana-Champaign, a 2011 Arthur C. Cope Scholar Award.
Burke’s “pioneering vision for molecular prosthetics has the potential to be revolutionary,” chemistry professor Stuart L. Schreiber of Harvard University notes. And his “nascent research program is already having a major impact on the field of organic synthesis, a trend that promises to continue far into the future,” he adds.
Burke’s concept for molecular prosthetics involves the replacement of functionally deficient proteins with small-molecule surrogates. A prototype for the development of such agents is the small-molecule natural product amphotericin B, which self-assembles into transmembrane ion-conducting aggregates.
A mechanism explaining how amphotericin B undergoes remodeling into an ion channel had been proposed, but in 2007 Burke and coworkers demonstrated that that model was itself in need of remodeling. By deleting key amphotericin B functional groups, they showed that a carboxylate that had been proposed to play a critical role in the mechanism was in fact not needed for channel self-assembly and ion transport. The researchers are currently trying to develop a highly efficient and flexible total synthesis of amphotericin B to provide access to derivatives for systematic structure-function studies.
Directly stimulated by the goal of achieving that total synthesis, Burke and coworkers recently devised a new synthetic strategy called iterative cross-coupling in which relatively simple molecular building blocks are combined into complex molecules with a single reaction type. The idea is to use bifunctional haloboronic acids like Lego pieces that combine by Suzuki-Miyaura reactions to assemble complex architectures.
In 2007, Burke and coworkers discovered that an inexpensive and environmentally benign ligand, methyliminodiacetic acid (MIDA), can control the reactivity of haloboronic acids and thus prevent them from combining in random ways. They used MIDA boronates to achieve the first total synthesis of the natural product ratanhine and to make challenging polyenes such as retinal, parinaric acid, and peridinin, in each case employing only a single reaction type to assemble the parts. They also used MIDA boronates to couple notoriously challenging substrates such as 2-pyridyl boronic acids.
Bristol-Myers Squibb and other pharmaceutical companies in the U.S. and Europe are using Burke’s boronates in drug discovery programs, and Sigma-Aldrich offers more than 70 MIDA boronates commercially.
Burke’s group is currently working to build a machine, similar to a peptide synthesizer, that would construct complex molecules via iterative coupling of MIDA boronates. “Achieving this goal would have substantial and broad impact, perhaps even extending the power of organic synthesis to the nonchemist,” Schreiber comments. The machine, he notes, is an “ambitious but now likely attainable goal.”
Burke, 34, earned a bachelor’s degree in chemistry at Johns Hopkins University in 1998, a Ph.D. in chemistry from Harvard in 2003, and an M.D. at Harvard Medical School and Massachusetts Institute of Technology in 2005. He was named a Howard Hughes Medical Institute Early Career Scientist in 2009.