
Contact Information
University of Illinois
454 RAL, Box 52-5
600 South Mathews Avenue
Urbana, IL 61801
Research Areas
Additional Campus Affiliations
Professor, Carle Illinois College of Medicine
Professor, Beckman Institute for Advanced Science and Technology
Department Affiliate, Biochemistry
Professor, Carl R. Woese Institute for Genomic Biology
Biography
Marty Burke completed a PhD in Chemistry at Harvard and a M.D. in the Health Sciences and Technology Program at Harvard Medical School and MIT. He is now the May and Ving Lee Professor for Chemical Innovation at UIUC and helped launch the Carle Illinois College of Medicine by serving as the inaugural Associate Dean for Research. Burke is a pioneer in the development of molecular prosthetics, automated small molecule synthesis, and renal-sparing polyene antifungals. His lab first showed that small molecules can replace deficient proteins and thereby restore physiology in animals, and in people, thus operating like prostheses on the molecular scale. He identified a molecular prosthetic for cystic fibrosis that achieved proof-of-concept in an investigator-initiated clinical trial, and one for anemias (advanced pre-clinical development). Burke further showed how the robustness of living systems interfaces with imperfect small molecule mimics to restore physiology. Burke’s lab also developed an automated lego-like platform for small molecule synthesis based on MIDA boronates that is increasingly general. His MIDA boronate chemistry has now been used by >250 academic and industrial labs worldwide to make a wide range of different natural products, pharmaceuticals, materials, and many other types of small molecules (>750 publications, >200 patent applications), and >270 of his MIDA boronates are commercially available. Burke’s group leveraged this platform to discover that the clinically vital but also highly toxic fungicidal natural product amphotericin B primarily kills cells by forming an extramembranous sterol sponge, a mechanism that had evaded the scientific community for more than half a century. This enabled Burke to rationally separate the ion channel-forming activity of this natural product to develop molecular prosthetics for cystic fibrosis, and to design a renal-sparing polyene antifungal (advanced preclinical development for life-threatening invasive fungal infections). Based on these advances, Burke (co)-founded four biotechnology companies [REVOLUTION Medicines (Nasdaq: RVMD), cystetic Medicines, Ambys Medicines, and Sfunga Therapeutics], which collectively have one drug candidate in Ph 2, and three more on track to begin clinical trials in 2023. And he co-founded the Molecule Maker Lab Institute that is broadly expanding access to automated small molecule synthesis. Burke also lead the SHIELD: Test, Target, and Tell program at UIUC that created and scalably deployed an FDA Emergency Use Authorized rapid saliva test for SARS-CoV-2, and strategically integrated it with state-of-the-art computational modeling and a custom-built app, to mitigate the spread of COVID-19 at UIUC. As a leader in COVID-19 testing, he also worked with NASEM Societal Experts Action Network, NASEM Naval Studies Board, U.S. Marine Corps, Council on Foreign Relations, American Public Health Association, Rockefeller Foundation and Office of the U.S. Assistant Secretary for Health. Burke also helped SHIELD Illinois and SHIELD T3 expand this testing platform to >1700 K-12 schools, colleges, universities, companies, and organizations throughout the U.S. and other countries, including New Zealand, Philippines, and Indonesia. Worldwide, greater than 10 million COVID-19 tests have been run to date.
Research Interests
Synthesis and study of small molecules with protein-like functions
Research Description
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.
Awards and Honors
- 2022 Fellow, American Association for the Advancement of Science
- 2021 Presidential Medallion, University of Illinois
- 2021 Johns Hopkins University Distinguished Alumnus Award
- 2021 LAS Impact Award, UIUC
- 2021 Member, American Society for Clinical Investigation
- 2019 iCON Award
- 2019 Mukaiyama Award, Japan
- 2017 American Chemical Society Nobel Laureate Award for Graduate Education
- 2014 Hirata Memorial Lectureship Award, Japan
- 2014 International Organic Chemistry Foundation Lectureship Award, Japan
- 2014 Thieme-IUPAC Prize in Synthetic Organic Chemistry
- 2013 Elias J. Corey Award for Outstanding Contribution in Organic Synthesis by a Young Investigator, American Chemical Society
- 2011 Arthur C. Cope Scholar Award, American Chemical Society
- 2010 Bristol-Myers Squibb Lectureship at Harvard University
- 2010 Novartis Lectureship at The University of California Berkeley
- 2010 Frontiers in Chemistry Lectureship at The Scripps Research Institute
Honors & Awards
2019 iCON Award
2019 Mukaiyama Award, Japan
2017 American Chemical Society Nobel Laureate Award for Graduate Education
2014 Hirata Memorial Lectureship Award, Japan
2014 International Organic Chemistry Foundation Lectureship Award, Japan
2014 Thieme-IUPAC Prize in Synthetic Organic Chemistry
2013 Elias J. Corey Award for Outstanding Contribution in Organic Synthesis by a Young Investigator, American Chemical Society
2011 Arthur C. Cope Scholar Award, American Chemical Society
2010 Bristol-Myers Squibb Lectureship at Harvard University
2010 Novartis Lectureship at The University of California Berkeley
2010 Frontiers in Chemistry Lectureship at The Scripps Research Institute
Highlighted Publications
Blair, D. J., Chitti, S., Trobe, M., Kostyra, D. M., Haley, H. M. S., Hansen, R. L., Ballmer, S. G., Woods, T. J., Wang, W., Mubayi, V., Schmidt, M. J., Pipal, R. W., Morehouse, G. F., Palazzolo Ray, A. M. E., Gray, D. L., Gill, A. L., & Burke, M. D. (Accepted/In press). Automated iterative Csp3-C bond formation. Nature. https://doi.org/10.1038/s41586-022-04491-w
Lewandowska, A., Soutar, C. P., Greenwood, A. I., Nimerovsky, E., De Lio, A. M., Holler, J. T., Hisao, G. S., Khandelwal, A., Zhang, J., SantaMaria, A. M., Schwieters, C. D., Pogorelov, T. V., Burke, M., & Rienstra, C. (2021). Fungicidal amphotericin B sponges are assemblies of staggered asymmetric homodimers encasing large void volumes. Nature Structural Biology, 28(12), 972-981. https://doi.org/10.1038/s41594-021-00685-4
Recent Publications
Angello, N. H., Rathore, V., Beker, W., Wołos, A., Jira, E. R., Roszak, R., Wu, T. C., Schroeder, C. M., Aspuru-Guzik, A., Grzybowski, B. A., & Burke, M. D. (2022). Closed-loop optimization of general reaction conditions for heteroaryl Suzuki-Miyaura coupling. Science, 378(6618), 399-405. https://doi.org/10.1126/science.adc8743
Beker, W., Roszak, R., Wolos, A., Angello, N. H., Rathore, V., Burke, M. D., & Grzybowski, B. A. (2022). Machine Learning May Sometimes Simply Capture Literature Popularity Trends: A Case Study of Heterocyclic Suzuki-Miyaura Coupling. Journal of the American Chemical Society, 144(11), 4819-4827. https://doi.org/10.1021/jacs.1c12005
Blair, D. J., Chitti, S., Trobe, M., Kostyra, D. M., Haley, H. M. S., Hansen, R. L., Ballmer, S. G., Woods, T. J., Wang, W., Mubayi, V., Schmidt, M. J., Pipal, R. W., Morehouse, G. F., Palazzolo Ray, A. M. E., Gray, D. L., Gill, A. L., & Burke, M. D. (2022). Automated iterative Csp3-C bond formation. Nature, 604(7904), 92-97. https://doi.org/10.1038/s41586-022-04491-w
Bubliauskas, A., Blair, D. J., Powell-Davies, H., Kitson, P. J., Burke, M. D., & Cronin, L. (2022). Digitizing Chemical Synthesis in 3D Printed Reactionware. Angewandte Chemie - International Edition, 61(24), [e202116108]. https://doi.org/10.1002/anie.202116108
Burke, M. D., & Grillo, A. S. (2022). Restoring Physiology In Iron-deficient Organisms Using Small Molecules. (U.S. Patent No. 11517540).