 Professor of Chemistry and Biochemistry
S.B. 1983, Massachusetts Institute of Technology
Ph.D. 1989, Yale University
Room: 5132
Phone: 608-262-0541
Email: kiesslin@chem.wisc.edu
Position: Professor
E. C. Dykhuizen, J. F. May, A. Tongpenyai, and L. L. Kiessling. Inhibitors of UDP-Galactopyranose Mutase Thwart Mycobacterial Growth. 2008, J. Am. Chem. Soc. 130, 6706-6707.
E. M. Kolonko and L. L. Kiessling. A polymeric domain that promotes cellular internalization. 2008, J. Am. Chem. Soc. 130, 5626-5627.
E. S. Underbakke, Y. Zhu, and L. L. Kiessling. Isotope-Coded Affinity Tags with Tunable Reactivites for Protein Footprinting. 2008, Angew. Chem. Int. Ed. 47, 9677-9680.
C. B. Carlson, P. Mowery, R. M. Owen, E. C. Dykhuizen and L. L. Kiessling. Selective Tumor Cell Targeting Using Low Affinity Multivalent Interactions. 2007, ACS Chem. Biol. 2, 119-127.
E. B. Puffer, J. K. Pontrello, J. J. Hollenbeck, J. A. Kink, and L. L. Kiessling. Activating B Cell Signaling with Defined Multivalent Ligands. 2007, ACS Chem. Biol. 2, 252-262.
L. L. Kiessling, J. E. Gestwicki and L. E. Strong (2006). Synthetic Ligands as Probes of Signal Transduction. 2006, Angew. Chem. Int. Ed. 45, 2348-2368.
J. K. Pontrello, M. J. Allen, E. S. Underbakke, and L. L. Kiessling. Solid-Phase Synthesis of Polymers Using the Ring-Opening Metathesis Polymerization. 2005, J. Am. Chem. Soc. 127, 14536-14537. Y. He, R. J. Hinklin, J. Chang and L. L. Kiessling . Stereoselective N-Glycosylation by Staudinger Ligation. 2004, Org. Lett. 6, 4479-4482.
M. L. Soltero-Higgin, E. E. Carlson, T. D. Gruber and L. L. Kiessling. A Unique Catalytic Mechanism for UDP-Galactopyranose Mutase 2004, Nature Mol. Struct. Biol. 11, 539-543.
T. Young and L. L. Kiessling. A Strategy for the Synthesis of Sulfated Peptides. 2002, Angew. Chem. Int. Ed. Eng. 41, 3449-3451.
J. E. Gestwicki, C. W. Cairo, L. E. Strong, K. A. Oetjen and L. L. Kiessling. Influencing Receptor - Ligand Binding Mechanisms with Multivalent Ligand Architecture. 2002, J. Am. Chem. Soc. 124, 14922-14933. C. R. Bertozzi and L. L. Kiessling. Chemical Glycobiology, 2001, Science 291, 2357-64.299
R. J. Hinklin and L. L. Kiessling. Glycosyl Sulfonylcarbamates: New Glycosyl Donors with Tunable Reactivity. 2001, J. Am. Chem. Soc. 123, 3379-3380. B. L. Nilsson, L. L. Kiessling and R. T. Raines (2000). Staudinger Ligation: A Peptide from a Thioester and Azide, Org. Lett. 2, 1939-1941. N. Maki, J. E. Gestwicki, L. L. Kiessling and J. Adler (2000). Motility and Chemotaxis of Filamentous Cells of Escherichia coli, J. Bacteriol. 182, 4337-4342. S. D. Burke, Q. Zhao, M. C. Schuster and L. L. Kiessling (2000). Synergistic Formation of Soluble Lectin Clusters by a Templated Multivalent Saccharide Ligand, J. Am. Chem. Soc 122, 4518-4519.
| Research Description
Our group develops and implements synthetic methods to access biologically-active compounds for hypothesis-driven and discovery-driven research. This important foundation of our program offers chemically-oriented researchers new opportunities to develop and apply their synthetic skills. Biochemically- and biologically-oriented researchers benefit from access to unique biologically active ligands. Some representative questions that drive our interdisciplinary research program follow.
I. What are the biological roles of carbohydrates? Carbohydrates can influence protein stability and protein trafficking; they also also are important in recognition and can act as signals. Illuminating the biological roles of carbohydrates stands as a major scientific forefront. Chemical synthesis is uniquely poised to address this challenge. In our initial forays into the array, we focused on synthesizing carbohydrates and glycoconjugates to explore their roles. These studies led to new discoveries about how sulfation influences carbohydrate recognition and the role of carbohydrate-binding proteins in embryo implantation. More recently, we are focused on finding non-carbohydrate inhibitors. These compounds can be used to block important protein-carbohydrate interactions or to inhibit specific carbohydrate biosynthetic enzymes. Some examples of the kinds of targets are shown in the Figure.
II. Can we exploit carbohydrate recognition for new purposes? We used the properties of carbohydrate recognition to devise a strategy to mediate selective killing of tumor cells. Our approach exploits the features of tumor cells, which are often distinguished from normal cells by their higher levels of particular cell surface receptors. We used a chemically-synthesized, small‑molecule composed of two distinct motifs: (1) a ligand that binds tightly (Kd ~ 10-9 M) to avb3 integrins, and (2) a carbohydrate (galactosyl-a(1-3)galactose or a‑Gal epitope), which is recognized by human anti-a‑galactosyl antibodies (anti-Gal). Importantly, anti-Gal antibodies are recruited when the bifunctional conjugate decorates a tumor cell possessing a high level of the target receptor (the avb3 integrin); anti-Gal then triggers cell killing. Tumor cell lines with high levels of the integrin receptor are killed (Figure). Our results have implications for the treatment of cancer and other diseases.
III. How do cells detect and respond to stimuli in the environment? The view from the surface of a cell reveals a complex milieu composed of membrane-associated proteins, lipids and carbohydrates. This surface of molecules is a remarkable conduit of information. The molecules on the surface have the critical role of reporting to the interior on extracellular conditions (e.g., presence of nutrients or toxins), so that the cell can respond appropriately. We have been designing chemical probes to understand the mechanisms underlying how molecular signals are processed.
Guggenheim Fellowship, 2008 Member, Wisconsin Academy of Sciences, Arts and Letters, 2008 Member, National Academy of Sciences, 2007 Member, American Academy of Microbiology, 2007 Francis P. Garvan-John M. Olin Medal, American Chemical Society, 2006 Tetrahedron Young Investigator Award, 2005 Harrison-Howe Award, Rochester ACS, 2005 Member, American Academy of Arts & Sciences, 2003 Fellow, American Association for the Advancement of Science, 2003 Carbohydrate Research Award, 2001 Romnes Faculty Fellowship, University of Wisconsin-Madison, 2001 Horace Isbell Award, Carbohydrate Division of the American Chemical Society, 2000 MacArthur Foundation Fellowship, 1999-2004 Selected as one of the 50 top R & D stars to watch by Industry Week, 1999 John D. and Catherine T. MacArthur Foundation Fellowship, 1999 Arthur C. Cope Scholar Award, 1999 National Science Foundation, National Young Investigator Award (NYI), 1993-98 Alfred P. Sloan Foundation Fellowship, 1997 Shaw Scientist Award, 1992-97 Dreyfus Teacher-Scholar Award, 1996 Zeneca Excellence in Chemistry Award, 1996 American Cancer Society Junior Faculty Award, 1995-97 Procter and Gamble University Exploratory Research Award, 1992-95 Beckman Young Investigator Award, 1994-96 American Cancer Society Postdoctoral Fellowship, 1989-91 Sigma Xi Scientific Research Society, 1983 Phi Lambda Upsilon Honorary Chemical Society, 1981
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