Departmental Affiliation(s): Chemical and Systems Biology and Chemistry
Graduate Program(s): Chemical and Systems Biology

Phone: 650 723-4005
Location: Clark Center, W350A
Email: wandless@stanford.edu
Website: http://wandless.stanford.edu/

Keywords:

organic synthesis, chemistry, chemical biology, biophysics, biochemistry, NMR spectroscopy, signal transduction, drug discovery, drug development

Research Description:

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.

For example, we are currently working on a new and general method to use synthetic molecules to regulate protein function.  Studies of mammalian development have been revolutionized by our ability to disrupt specific genes using homologous recombination in animals (e.g., knock-out mice). However interpreting the phenotypes of these mice is often difficult due to embryonic lethality or to cellular/molecular compensation for the missing gene during development. By targeting the protein directly rather than its gene, we have developed a general method to regulate the stability (and thus function) of specific proteins using a synthetic molecule. This new technique allows us to rapidly and reversibly eliminate a specific protein either in cell culture or in living mice.

In another area, we have devised a method to improve binding events between proteins and synthetic ligands 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.

Representative Publications:

1. "The Total Synthesis of Ustiloxin D and Considerations on the Origin of Selectivity of the Asymmetric Allylic Alkylation." Sawayama, A. M.; Tanaka, H.; Wandless, T. J., submitted.

2. "Quantitative Analyses of Bifunctional Molecules." Braun, P. D. and Wandless, T. J. Biochemistry, 2004, 43, 5406-5413.

3. "Conditional Protein Alleles Using Knock-in Mice and a Chemical Inducer of Dimerization." Stankunas, K.; Bayle, J. H.; Gestwicki, J. E.; Lin, Y.-M.; Wandless, T. J.; Crabtree, G. R. Molecular Cell , 2003, 12, 1615-1624.

4. "A Bifunctional Molecule That Displays Context-Dependent Cellular Activity." Braun, P. D.; Barglow, K. T.; Lin, Y.-M.; Akompong, T.; Briesewitz, R.; Ray, G.; Haldar, K.; Wandless, T. J.   J. Am. Chem. Soc., 2003, 125, 7575-7580.

5. "Enantioselective Total Synthesis of Ustiloxin D." Tanaka, H.; Sawayama, A.; Wandless, T. J. J. Am. Chem. Soc., 2003, 125, 6864-6865.