Zan Luthey-Schulten, Taras Pogorelov, Chad Rienstra, and Martin Burke represent two of 34 teams who have received allocations of computation time on the Blue Waters supercomputer.
Martin D. Burke
Professor Burke completed his undergraduate studies at Johns Hopkins University in 1998 and his Ph.D. at Harvard University in 2003. After completing an M.D. at Harvard Medical School, he joined the faculty in the Department of Chemistry at the University of Illinois in June of 2005. His research interests are in the area of organic chemistry with a specific focus on the synthesis and study of small molecules with protein-like functions.
- synthesis and study of small molecules with protein-like functions
Research in the Burke group focuses on the synthesis and study of small molecules with the capacity to perform protein-like functions. Ultimately, we envision such compounds serving as substitutes for missing or dysfunctional proteins, thereby operating as prostheses on the molecular scale. To enable these studies, we seek to develop new strategies and methods that make the process of complex small molecule synthesis as simple, efficient, and flexible as possible. We further aim to harness the power of this chemistry to illuminate the underpinnings of higher-order small molecule function in atomistic detail. Collectively, these efforts seek to make possible the development of molecular prosthetics as a general strategy for the understanding and betterment of human health. Specific examples of ongoing projects are described below:
Iterative Cross-Coupling (ICC): Towards a General Strategy for Complex Small Molecule Synthesis
To most effectively harness the potential impact of complex small molecules on both science and medicine, it is critical to maximize the simplicity, efficiency, and flexibility with which these types of compounds can be synthesized in the laboratory. In this regard, modern peptide synthesis, involving the iterative coupling of bifunctional amino acids represents a valuable benchmark. Amino acid building blocks are now commercially-available in suitably-protected form as stable, crystalline solids, and the process of peptide synthesis is routinely automated. As a result, this powerful discovery engine is accessible to a broad range of scientists. In sharp contrast, the laboratory synthesis of small molecules remains a relatively complex and non-systematized process. We are currently developing a simple and highly modular strategy for making small molecules which is analogous to peptide synthesis and involves iterative Suzuki-Miyaura cross-coupling of B-protected haloboronic acids. In this approach, building blocks are prepared (or in the future simply purchased) having all of the required functional groups preinstalled in the correct oxidation state and with the desired stereochemical relationships. These building blocks are then brought together via the recursive application of one mild reaction. Although certain small molecules are currently more amenable to this approach than others, the rapidly expanding scope of the Suzuki-Miyaura reaction, which increasingly includes sp3-sp3 couplings, suggests the potential for broad generality. Our long term goal is to create a general and automated process for the simple and flexible construction of a broad range of complex small molecules.
Towards the Total Synthesis of Amphotericin B via Iterative Cross-Coupling
The channel-forming natural product amphotericin B is a prominent example of the special utility that may be found in small molecules that perform higher-order functions. Specifically, in contrast to most antibiotics, microbial resistance to amphotericin B is extremely rare, and it is likely that the lack of a mutable protein target and lack of resistance are causatively linked. This relationship may prove to be general and merits intense inquiry. Moreover, in many ways amphotericin B represents a potential prototype for small molecules that replicate the functions of protein-based ion channels and thereby operate as prostheses on the molecular scale. However, despite more than five decades of research, the archetypal amphotericin B channel remains poorly understood at the molecular level precluding the rational pursuit of these objectives. An efficient, modular, and flexible total synthesis of this complex natural product stands to enable the first systematic dissection of the structure/function relationships that underlie its extraordinary ion channel activity. Taking advantage of the iterative cross-coupling strategy described above, we aim to synthesize amphotericin B using only the Suzuki-Miyaura reaction to bring together a collection of efficiently synthesized bifunctional building blocks.
Harnessing the Power of Synthesis to Probe the Structure and Function of the Amphotericin B Ion Channel
Molecular modeling studies predict that specific protic functional groups appended to the amphotericin B macrolide skeleton make important contributions to the self-assembly and/or ion transport properties of this prototypical small molecule-based ion channel. We aim to harness the power of organic synthesis to systematically test these hypothetical structure/function relationships. More specifically, we are employing a variety of approaches including total synthesis (described above), degradation of the natural product, and a hybrid semisynthetic approach to prepare a collection of amphotericin B derivatives that each lack one or more of the appended polar functional groups. We have found using multidimensional NMR techniques that the conformation of the macrolide skeleton is unaltered by these types of appendage deletions, greatly facilitating the interpretation of structure/function studies. Using the degradative synthetic approach, we have recently discovered that, in stark contrast to the leading model for channel self-assembly, oxidation at C(41) of the amphotericin B skeleton is not required for potent antifungal activity. Systematic evaluation of the complete collection of targeted derivatives in a battery of biological and biophysical assays stands to produce, for the first time, an atomistic understanding of the self-assembly and conducting properties of the potentially prototypical amphotericin B ion channel.
Distinctions / Awards
- 2017 American Chemical Society Nobel Laureate Award for Graduate Education
- 2014 Hirata Memorial Lectureship Award, Japan
- 2014 Thieme-IUPAC Prize in Synthetic Organic Chemistry
- 2014 International Organic Chemistry Foundation Lectureship Award, Japan
- 2013 Elias J. Corey Award for Outstanding Contribution in Organic Synthesis by a Young Investigator, American Chemical Society
- Arthur C. Cope Scholar Award, American Chemical Society, 2011
- Bristol-Myers Squibb Lectureship at Harvard University, 2010
- Frontiers in Chemistry Lectureship at The Scripps Research Institute, 2010
- Novartis Lectureship at The University of California Berkeley, 2010
In The News
The first-of-its-kind Molecule Maker Lab, part of the Medical Maker Lab at Illinois, will empower physician-innovators at the Carle Illinois College of Medicine, and citizen scientists from around the world, to create molecules on-demand.
Professor Burke has been named University Scholar, a program that recognizes excellence in teaching, scholarship and service. Read more>>
Martin Burke was announced as an inaugural faculty of the Carle Illinois College of Medicine.
Martin Burke proposes billion-dollar project to synthesize most of the hundreds of thousands of known organic natural products in search of new medicines.