Associate Professor (b. 1966)
B.S., 1988, Trinity University; Ph.D., 1993, Harvard University
NSF Postdoctoral Fellow, 1993-1995, Harvard Medical School; Dreyfus New Faculty
Award, 1995; Beckman Foundation Investigator, 1998; Phi Beta Kappa Teaching
Award, 1998. Sloan Foundation Fellowship, 2000; Dreyfus Teacher-Scholar, 2000
Organic and Biological Chemistry
650-723-4005
wandless@chem.stanford.edu
Wandless Group
The overarching goals of our research program lie at the interface of chemistry and biology. Specifically, we focus on the design and synthesis of molecules that allow us to learn about and control specific cellular processes. The underlying basis for our research is an understanding of the factors that govern the strength and specificity of molecular interactions.
Organic molecules often bind to their protein targets with only moderate affinity. We have devised a method to improve these binding events by borrowing additional surface area from abundant cellular proteins. We use synthetic chemistry to prepare bifunctional molecules that are capable of binding to two different proteins simultaneously. The resulting trimeric complexes possess additional protein-protein interactions that may contribute favorably to the overall stability of the complex.
Bifunctional molecules may also be used to diminish the affinity of an organic compound for its protein receptor. We have used this approach to detoxify bifunctional molecules in human cells that are otherwise cytotoxic to microorganisms. In mammalian cells, the bifunctional molecule binds preferentially to a protective cellular protein, thus sequestering the cytotoxic ligand away from its protein target. In bacteria, which lack the protective protein, only the cytotoxic half of the bifunctional molecule binds to its protein target resulting in selective bacterial death.
In many cases the molecules that we synthesize serve as probes of biological processes, particularly related to signal transduction and the role that the cytoskeleton plays in cellular signaling. For example, phomopsin A is the most potent microtubule-depolymerizing agent yet identified. We are synthesizing phomopsin as well as variants of the natural product that are designed to probe the requirements for microtubule depolymerization and cytotoxic activity. These compounds exhibit cellular effects that we use to study components of the cytoskeleton and its associated signaling pathways.
1 “Calcineurin Inhibitors and the Generalization of the Presenter Protein Strategy.” Vogel, K. W.; Briesewitz, R.; Wandless, T.J.; Crabtree, G. R. In Advances in Protein Chemistry; E.M. Scolnick, Ed.; Academic Press: San Diego, CA, 56, 253-291 (2001).
2 “Mechanistic Studies of Affinity Modulation.” Rosen, M.K.; Amos, C.D.; Wandless, T.J. J. Am. Chem. Soc., 122, 11979-11982 (2000).
3 “A Confederacy of Bunches: Fundamentals and Applications of a Self-Associating Protein,” T.J. Wandless, Proc. Natl. Acad. Sci. USA, 97, 6921-6923 (2000).
4 “Affinity Modulation of Small-Molecule Ligands by Borrowing Endogenous Protein Surfaces,” R. Briesewitz, G.T. Ray, T.J. Wandless, and G.R. Crabtree, Proc. Natl. Acad. Sci. USA, 96, 1953-1958 (1999).
5 “A Stereospecific Elimination to Form Dehydroamino Acids: Synthesis of the Phomopsin Tripeptide Sidechain,” M.M. Stohlmeyer, H. Tanaka, and T.J. Wandless, J. Am. Chem. Soc., 121, 6100-6101 (1999).