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Martin D. Burke

Profile picture for Martin D. Burke

Contact Information

Office Managers
Kyla Lacy: kylalacy@illinois.edu
Marcia Fonseca: marciaaf@illinois.edu

Department of Chemistry
University of Illinois
454 RAL, Box 52-5
600 South Mathews Avenue
Urbana, IL 61801
May and Ving Lee Professor for Chemical Innovation, and Professor of Chemistry

Biography

Martin Burke is pioneering the Lego-like synthesis of small molecules. In contrast to the traditional complex and customized approach, Burke has demonstrated that his simple and increasingly general Lego-like platform for making small molecules is well-suited for automation and integration with artificial intelligence, thus opening a path toward democratized molecular innovation. His chemistry has been used by hundreds of academic and industrial labs around the world to make a wide range of different natural products, pharmaceuticals, and materials, and many of his boronate building blocks are commercially available. In his own lab, Burke leveraged this Lego-like chemistry to launch the field of molecular prosthetics and discover renal sparing antifungals. His group specifically identified a molecular prosthetic for cystic fibrosis that has reached the stage of a successful first clinical trial in people with CF, and additional molecular prosthetics for anemia and neurodegeneration which are at advanced stages of pre-clinical development. His group illuminated how the robustness of living systems interfaces with imperfect small molecule mimics to restore physiology, and has also leveraged this molecular prosthetics approach to better understand how loss of protein function causes human diseases. Burke also helped launch the Carle Illinois College of Medicine and served as its inaugural Associate Dean of Research. In this role, he led the SHIELD program for mitigating SARS-CoV-2 transmission at UIUC using a novel rapid-result COVID-19 saliva test, and in Fall 2020 there were hundreds of fewer COVID-related deaths relative to expected in Champaign County. During the pandemic, Burke advised the U.S. Center for Disease Control, U.S. Marine Corps, Council on Foreign Relations, American Public Health Association, Rockefeller Foundation, National Academy of Science Engineering and Medicine, Office of the U.S. Assistant Secretary of Health, White House COVID-19 Response Team, and Biden Presidential Transition Team, along with many K-12 schools, colleges, and universities. The SHIELD saliva test has now been deployed >20 million times in schools, colleges, universities, businesses, and many other communities worldwide. Burke is a member of the National Academy of Medicine and the American Society for Clinical Investigation, and a Fellow of the American Association for the Advancement of Science. He received the Nobel Laureate Signature Award for Graduate Education in Chemistry, the Yoshimasa Hirata Memorial Gold Medal, the Mukaiyama Award, the Elias J. Corey Award for Outstanding Original Contribution in Organic Synthesis by a Young Investigator, the Arthur C. Cope Scholar Award, and a Presidential Medallion from the University of Illinois, and he has been recognized many times as a Teacher Ranked as Excellent. Burke is the scientific founder of four biotechnology companies with five drug candidates that have entered clinical trials. He received his undergraduate education at Johns Hopkins University, a PhD at Harvard University, and an MD at Harvard Medical School and the Massachusetts Institute of Technology. Burke is the founding Director of the Molecule Maker Lab at the Beckman Institute for Advanced Science and Technology and a founding member of the Molecule Maker Lab Institute at the Carl R. Woese Institute for Genomic Biology. Burke is now the May and Ving Lee Professor for Chemical Innovation in the Department of Chemistry at the University of Illinois at Urbana-Champaign.

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 formationNaturehttps://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 volumesNature Structural Biology28(12), 972-981. https://doi.org/10.1038/s41594-021-00685-4

 

Recent Publications

Angello, N. H., Friday, D. M., Hwang, C., Yi, S., Cheng, A. H., Torres-Flores, T. C., Jira, E. R., Wang, W., Aspuru-Guzik, A., Burke, M. D., Schroeder, C. M., Diao, Y., & Jackson, N. E. (2024). Closed-loop transfer enables artificial intelligence to yield chemical knowledge. Nature, 633(8029), 351-358. https://doi.org/10.1038/s41586-024-07892-1

Blake, A. D., Chao, J., SantaMaria, A. M., Ekaputri, S., Green, K. J., Brown, S. T., Rakowski, C. K., Choi, E. K., Aring, L., Chen, P. J., Snead, N. M., Matje, D. M., Geng, T., Octaviani, A., Bailey, K., Hollenbach, S. J., Fan, T. M., Seo, Y. A., & Burke, M. D. (2024). Minimizing higher-order aggregation maximizes iron mobilization by small molecules. Nature chemical biology, 20(10), 1282-1293. https://doi.org/10.1038/s41589-024-01596-3

Burke, M. D., Denmark, S. E., Diao, Y., Han, J., Switzky, R., & Zhao, H. (2024). Molecule Maker Lab Institute: Accelerating, advancing, and democratizing molecular innovation. AI Magazine, 45(1), 117-123. https://doi.org/10.1002/aaai.12154

Klucznik, T., Syntrivanis, L. D., Baś, S., Mikulak-Klucznik, B., Moskal, M., Szymkuć, S., Mlynarski, J., Gadina, L., Beker, W., Burke, M. D., Tiefenbacher, K., & Grzybowski, B. A. (2024). Computational prediction of complex cationic rearrangement outcomes. Nature, 625(7995), 508-515. https://doi.org/10.1038/s41586-023-06854-3

Strieth-Kalthoff, F., Hao, H., Rathore, V., Derasp, J., Gaudin, T., Angello, N. H., Seifrid, M., Trushina, E., Guy, M., Liu, J., Tang, X., Mamada, M., Wang, W., Tsagaantsooj, T., Lavigne, C., Pollice, R., Wu, T. C., Hotta, K., Bodo, L., ... Aspuru-Guzik, A. (2024). Delocalized, asynchronous, closed-loop discovery of organic laser emitters. Science, 384(6697), Article eadk9227. https://doi.org/10.1126/science.adk9227

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